线粒体 Nicolas Verhoeven

线粒体是细胞的“动力工厂”，能够产生细胞所需的大部分能量，为身体运动以及维持生命所需的所有生化过程提供能量。与 PHYSIONIC 的 Nicolas Verhoeven 博士探讨什么是线粒体，以及与多种慢性疾病（例如 2 型糖尿病、心脏病、中风、神经退行性疾病以及亨廷顿氏病等遗传/基因疾病）的关系。还详细探讨了可以采取哪些饮食和生活方式来保持线粒体健康并发挥最佳效率。

视频开场与主题介绍 (00:00 - 00:55)

主持人 Mario Kratz (Nourished by Science 频道主) 开场，点出本期视频的主题是线粒体 (mitochondria) 以及线粒体功能障碍 (mitochondrial dysfunction)。

线粒体功能障碍的普遍性：大多数慢性疾病中常见的细胞特征。
- 见于胰岛素抵抗的肝脏和肌肉细胞，以及无法分泌足够胰岛素的胰腺β细胞。
- 因此，有理由认为线粒体功能障碍是2型糖尿病发展中的关键细胞过程。
- 实际上，几乎所有慢性疾病，从心脏病到癌症再到神经退行性疾病，线粒体功能障碍似乎都在其中扮演一定角色。
本期焦点：与嘉宾 Dr. Nicholas Verhoeven (以下简称 Nick) 探讨个人可以做些什么来保持线粒体的健康和快乐。

嘉宾介绍与开场寒暄 (01:00 - 01:30)

Mario 欢迎 Nick 来到 Nourished by Science 频道。
Nick 表示非常荣幸，并称 Mario 是他获取营养和科学信息的三大主要来源之一。

线粒体的基本功能与重要性 (01:30 - 03:38)

介绍线粒体的基本情况。 Nick 解释：

细胞器 (Organelle)：线粒体是细胞内的一种细胞器。细胞由数十亿细胞组成，大多数细胞（非全部）含有细胞器。细胞器是细胞内具有特定功能的结构，可以看作细胞内的“工厂”或不同系统。
“细胞的动力工厂” (Powerhouse of the cell)：这是线粒体最广为人知的功能，即为细胞产生能量。
其他重要功能：
- 细胞信号传导 (Cell signaling)：线粒体能与其他细胞器、酶和功能蛋白交流，确保细胞正常运作。
- 产生其他化合物：不仅仅是能量。
- 隔离或吸收分子/离子：维持细胞内平衡。
- 生物合成 (Biosynthesis)：产生新分子，用于激素生产（如皮质醇、睾酮、雌激素都依赖线粒体）。
- 癌症防护 (Protect us from cancer)：当细胞功能失常并开始癌变时，细胞自身有自杀机制。线粒体也参与这一过程，通过不同触发机制，最终导致异常细胞死亡，从而阻止癌症发展。
能量在细胞过程中的广泛作用：线粒体产生的化学能不仅用于肌肉运动，还为细胞内所有其他过程提供能量，如物质运输、酶促反应、DNA到蛋白质的转化等。功能失常的线粒体导致所有这些过程能量不足。

线粒体功能障碍的定义与评估 (03:38 - 07:15)

Mario 引入“线粒体功能障碍”这一术语，询问其含义。 Nick 从三个层面解释：

顶层定义：线粒体功能不在正常范围内。
研究者评估层面：通过特定指标衡量线粒体功能。
* 耗氧量 (Oxygen consumption)：产生能量需要消耗氧气。测量分离出的线粒体（或细胞层面）的耗氧率是评估其健康状况的一种方式。耗氧率高通常是功能良好的标志，但需结合其他指标。

* ATP生成 (ATP generation)：ATP（三磷酸腺苷）是细胞主要的能量货币。直接测量ATP生成量是更直接的评估方法。
非能量相关的线粒体功能障碍：
* 膜电位丧失 (Loss of membrane potential)：线粒体有内外两层膜。线粒体基质（最内层）应比线粒体外部（仍在细胞内）更负电。如果这种电位差消失（内部正电性增加），线粒体将停止运作，并可能进入线粒体死亡（通常通过线粒体自噬，mitophagy）。

* 线粒体自噬缺陷 (Defective mitophagy)：即使线粒体失去膜电位，自噬机制也可能无法正常启动并清除受损线粒体。

* 蛋白质毒性 (Proteotoxicity)：功能异常的蛋白质在线粒体外膜或内部基质过度积累，影响线粒体正常功能。这些蛋白质可能是错误靶向到线粒体的，或者本身就是功能失常的。

* 物理损伤 (Physical damage)：过量的活性氧 (Reactive Oxygen Species, ROS) 等损伤性分子会破坏线粒体的化学完整性。注意：线粒体也会产生少量ROS用于细胞信号传导，只有过量ROS（氧化应激）才是有害的。

* 钙缓冲能力缺乏 (Lack of calcium buffering)：也是功能障碍的一种表现。

导致线粒体功能障碍的因素 (07:15 - 09:00)

Mario 问哪些因素会导致个体在特定组织或全身出现线粒体功能障碍，以及这些因素如何通过细胞内机制起作用。

Nick 列举了一些因素：

过量活性氧生成 (Excess reactive oxygen species generation)。
遗传因素 (Genetics)：有些人天生存在线粒体功能障碍，严重程度不一。
- 可能导致身体发育异常。
- 轻微的遗传缺陷可能在特定情况下显现。
- 一些已知的线粒体疾病，如MIOS、MELAS，源于特定基因的缺失或突变。
- 遗传性疾病的表型：可能表现为脂肪酸在细胞内积累（例如，与胰岛素抵抗相关），或细胞凋亡（程序性细胞死亡），影响肝脏、大脑、眼睛等各种器官。不同组织对线粒体的依赖程度不同，因此受影响程度也不同。
- 与特定疾病的关联：
  - 亨廷顿病 (Huntington's disease)：亨廷顿蛋白 (huntingtin) 异常积累在线粒体上，阻止其正常运作。
  - 阿尔茨海默病 (Alzheimer's disease)：也与线粒体功能障碍有关，但Nick强调并非所有疾病都完全归因于线粒体，研究者容易将所有问题归咎于自己的研究领域。

可控的生活方式因素与线粒体健康 (09:00 - 13:05)

哪些我们可以自己控制的饮食、生活方式或其他暴露因素，会通过上述机制影响线粒体健康，特别是导致氧化应激。

Nick 重点讨论两个主要可控因素，并结合线粒体内膜上的电子传递链（五个主要蛋白质复合物）来解释：

电子传递链的工作原理：营养物质（来自饮食、脂肪细胞、血糖）作为底物被输送到第一个蛋白质复合物，然后通过一系列链式反应最终产生能量。
能量需求与底物供应失衡：如果细胞能量需求不高，但底物供应过多，会导致“电子渗漏”(electron slippage)，产生过量ROS。
两个关键干预点：
1. 减少底物供应 (Reduce substrate)：通过控制饮食摄入。
  * 核心问题是过量消耗 (Overconsumption)：任何形式的过量消耗导致体重增加，都会引发过度的氧化应激，进而导致多种疾病。
2. 创造代谢汇 (Create a metabolic sink)：快速消耗ATP，使线粒体有“空间”产生ATP。
  * 运动是主要的ATP消耗方式：特别是肌肉运动。Nick引用其硕士课程中教授的说法，正常情况下人每天消耗约40公斤ATP，而剧烈运动（如马拉松）时会翻倍至80公斤。这种巨大的能量需求能“解放”线粒体，使其有效利用底物产生ATP，大大减少ROS的产生。
  
  * Nick提醒，这只是对细胞内生化反应的简化描述，并非线粒体“有意识地”选择。
过量饮食、脂肪异位储存与线粒体功能障碍 (13:05 - 15:35)

Mario 与他之前的视频内容联系起来，详细阐述过量饮食如何导致线粒体功能障碍：

热量过剩与皮下脂肪储存：长期过量摄入热量，身体首先将多余热量以脂肪形式储存在全身的皮下脂肪组织中，这是相对安全的长期脂肪储存方式。
个人脂肪阈值 (Personal fat threshold)：当皮下脂肪组织储存已满，无法进一步扩张时，就达到了个人脂肪阈值。
脂肪异位储存 (Ectopic fat storage)：超过阈值后，多余脂肪（来自饮食或碳水化合物转化）被迫储存在不适合长期储存脂肪的组织中，如腹腔内脏脂肪，以及肌肉、胰腺、肝脏等器官内。
底物过剩与线粒体损伤：这些异位储存的脂肪分子（脂肪酸）以及可能过剩的葡萄糖，成为线粒体的过量底物，导致线粒体功能障碍，部分原因是通过增加ROS产生和氧化应激。

关于这个过程的因果关系：是脂肪在肌肉等组织中积累导致线粒体功能障碍，还是功能失常的线粒体导致脂肪积累？

Nick 答：

可能取决于具体疾病状态或情况：有时是营养物质过度积累影响线粒体，有时是线粒体本身功能缺陷导致营养物质积累。
一项关键研究：多年前的一项研究，将健康的线粒体暴露于不同类型的脂肪（等量但类型不同）。
- 不饱和脂肪：对线粒体通常有良好影响，线粒体形态（从线性有序到高度碎片化）和行为表现正常。
- 饱和脂肪（特别是棕榈酸酯，palmitate，是最常见的饱和脂肪）：即使线粒体最初正常，加入棕榈酸酯后，线粒体开始大量产生氧化应激，激活多种应激酶，细胞最终损伤死亡。
- 这至少部分证明了特定营养分子可以直接影响线粒体并造成损害。但Nick也承认因果关系可能反过来。

Mario 总结 Nick的观点是，即使拥有健康的线粒体，一旦超过个人脂肪阈值，脂肪在肌肉、肝脏等组织中异位积累，这种过量的底物本身就可能导致线粒体功能障碍。但也可能存在其他因素先导致线粒体功能障碍，进而加剧脂肪在细胞内的积累。

组织特异性与线粒体功能 (15:35 - 19:00)

不同组织的细胞对脂肪的耐受性不同。

脂肪细胞：天生适合储存大量脂肪。皮下脂肪细胞在显微镜下看，几乎被一个巨大的脂肪滴（甘油三酯）充满，但这种大量的脂肪积累似乎并不会导致其线粒体功能障碍。
肌肉细胞或肝细胞：即使是少量的脂肪积累，也可能对其线粒体造成严重破坏。

Nick 评：

肌肉细胞中的脂滴 (Lipid droplets)：
- 训练有素的个体：肌肉中也会出现脂滴，但这些脂滴位于肌纤维内部（肌原纤维间），且紧邻线粒体。据信这是为了高效地将脂肪酸输送给线粒体供能。
- 糖尿病或肥胖个体：肌肉中也会积累脂滴，但这些脂滴倾向于位于细胞表面，并与更严重的胰岛素抵抗相关。
- 这表明，即使是相同的现象（脂滴积累），其位置和与线粒体的关系不同，导致的生理结果也完全不同。
脂肪细胞的复杂性：脂肪细胞本身也存在亚型（如米色脂肪、棕色脂肪），棕色脂肪与线粒体的关系密切（富含线粒体用于产热），而白色脂肪则不同。
结论：线粒体对细胞环境（包括周围脂肪）的反应方式非常复杂，存在许多有待探索的领域。

Mario 总结 Nick 的观点：对于耐力运动员而言，肌肉内脂滴的形成是一种精心策划的适应性过程，为运动提供能量储备。而对于胰岛素抵抗和糖尿病患者，这更像是一种意外的、被迫的脂肪沉积。Nick 认为这种理解是合理的。他还提到，肥胖个体脂肪细胞周围的脂肪交换非常剧烈，脂肪细胞似乎无法有效储存脂肪，不断“吐出”脂肪。免疫细胞甚至会聚集在脂肪细胞周围并吞噬脂肪，其具体机制尚不清楚，但可能与帮助氧化部分脂肪有关。血液中较高的甘油三酯水平也可能导致脂肪在肌肉和其他瘦组织中积累。

运动对ATP消耗和线粒体健康的额外益处 (19:00 - 22:05)

回到之前讨论的ATP消耗问题，Mario 指出运动（即使只是每天长时间散步）会增加肌肉细胞对ATP的需求，从而促进底物（葡萄糖、脂肪酸）的消耗，减少ROS的产生。 Nick 补充了运动的额外益处：

ATP到ADP和AMP的转化：剧烈运动导致ATP大量消耗，转化为ADP（二磷酸腺苷），甚至AMP（一磷酸腺苷）。
AMPK的激活：ADP和AMP水平的显著升高会激活AMPK（AMP活化蛋白激酶）。
PGC-1α的激活：AMPK进而激活PGC-1α（过氧化物酶体增殖物激活受体γ辅激活因子1α）。
线粒体生物合成 (Mitochondrial biogenesis)：PGC-1α是最有效的线粒体生物合成因子，能刺激细胞产生更多新的线粒体。
适应性效应：这种由运动引起的短暂“应激”（ATP骤降）导致细胞产生更多线粒体，从而增强细胞未来产生ATP和应对运动负荷的能力，形成累积效应。这是单纯通过营养调节难以达到的效果。

总结线粒体健康的关键因素与个人行动 (22:05 - 24:28)

Mario 总结前面的讨论：

避免慢性热量过剩：一旦超过个人脂肪阈值，葡萄糖和脂肪酸在肌肉、胰腺、肝脏甚至大脑等组织中积累，导致线粒体无法有效代谢这些过量底物，这与胰岛素抵抗直接相关，并通过增加ROS产生导致线粒体功能障碍。
* 行动：通过健康的饮食方式，避免慢性热量超标。如果已存在超出个人脂肪阈值的过量脂肪，应尽力去除。
规律运动：增加线粒体对ATP的需求，促进底物顺畅燃烧，减少ROS产生，保持现有线粒体健康，并通过ATP消耗信号刺激新线粒体的生成。
* 行动：规律运动，包括正式锻炼（跑步、力量训练）和减少久坐时间（如每隔一段时间起来活动、散步、做几个深蹲）。

VO2 max（最大摄氧量）是否可以作为衡量线粒体健康的整体指标，即通过保持线粒体健康和增加线粒体数量来提高VO2 max。

Nick 答：

可以将VO2 max视为线粒体功能的“人体代理指标”，但并非一一对应。低VO2 max也可能由肺部或心血管问题引起。
但在其他系统相对健康的前提下，VO2 max确实反映了整个氧气输送和利用链条的效率，最终氧气在肌肉线粒体中用于产生运动所需的能量。因此，两者之间存在明确关系。

其他影响线粒体健康的因素 (24:28 - 28:55)

除了底物过剩和缺乏运动，还有其他因素与线粒体健康相关。

近红外光 (Near-infrared light)：Nick表示他看过相关研究，但对其对照设计的严谨性持保留态度。尽管如此，一些研究表明红光或近红外光能作用于线粒体，似乎能提高线粒体效率，可能直接影响电子传递链上的蛋白质，或通过线粒体的逆行信号传导 (retrograde signaling) 影响整个细胞。
多酚与抗氧化剂 (Polyphenols and antioxidants)：富含抗氧化剂的食物（如水果、蔬菜、可可/黑巧克力）有益于线粒体。当其他因素导致氧化应激增加时，这些抗氧化剂可以帮助“平息”线粒体内部的“燃烧”。运动本身也能刺激线粒体产生内源性抗氧化系统。
减少棕榈酸酯类饱和脂肪的摄入。
维护其他身体系统的健康，特别是心血管系统：
- 缺氧与再灌注损伤 (Reperfusion injury)：当冠状动脉阻塞导致心肌缺氧时，线粒体无法产生能量。如果突然恢复血流，大量氧气涌入会使线粒体产生爆发性的ROS，造成再灌注损伤。
- 启示：改善动脉粥样硬化风险，保持心血管健康，也是维护线粒体健康的重要途径。许多有益于心血管健康的措施也直接有益于线粒体。

线粒体功能障碍的组织特异性 (28:55 - 31:08)

Mario 提问，不同疾病中观察到的线粒体功能障碍（如胰腺β细胞、胰岛素抵抗的肝细胞和肌肉细胞、神经退行性疾病的脑区）是否是同一种类型，还是存在组织特异性？ Nick 的观点（基于有根据的推测）：

可能存在显著差异：不同疾病状态和不同组织中的线粒体功能障碍类型很可能不同。
遗传研究的证据：遗传性线粒体疾病（如亨廷顿病中特定蛋白质的积累）与肥胖相关的线粒体功能障碍（更多与营养过剩或缺乏运动相关）的机制就不同。
运动改善胰岛素抵抗：缺乏运动会导致ROS增加、线粒体数量减少、线粒体自噬功能下降，从而引发功能障碍。
因此，他推测线粒体功能障碍的类型会因组织而异。

如何检测线粒体功能障碍 (31:08 - 33:08)

Mario 询问普通人是否有方法检测自己是否存在线粒体功能障碍。 Nick 的回答：

存在检测方法，但各有优劣：
- 一些公司检测线粒体蛋白质（如电子传递链上的五种蛋白）的总量，Nick认为这不是衡量线粒体功能的良好指标，只能说明蛋白质数量，不能说明功能。
- 梅奥诊所 (Mayo Clinic) 提供基因阵列检测，专门针对与线粒体疾病高度相关的基因，可以检测突变情况，但这并非常规可及的检测。
组织样本的局限性：即使获取皮肤、成纤维细胞或肌肉样本进行检测，结果也未必能代表全身所有细胞的情况。
常规可及检测的缺乏：目前没有简便易行的常规方法来准确测量线粒体功能或功能障碍。
VO2 max作为间接指标：如前所述，可以作为一种方式，但非一一对应。
实验室研究：可以通过参与科研项目获得检测，但非普适。
测量的复杂性：测量线粒体功能本身非常困难，因为需要考虑的变量太多。

测量困难对科研的阻碍 (33:08 - 36:15)

Mario 指出，测量线粒体功能的困难也阻碍了相关科研进展。例如，他自己过去的临床干预试验中，并未将肌肉或肝脏的线粒体功能作为终点指标，因为难以测量。这导致我们对因果关系（如什么因素先发生）的理解仍不完善，许多研究依赖动物实验、横断面研究或细胞培养。

Mario 总结本期对话的核心内容：

我们已经对线粒体有了相当的了解，线粒体对细胞乃至整个身体的正常功能至关重要。
保持线粒体健康的已知因素，与保持整体健康、感觉良好、降低慢性病风险的因素高度一致。
对线粒体健康不利的因素：
1. 慢性热量过剩。
2. 缺乏体育活动（慢性久坐行为，从不锻炼）。
3. 低抗氧化剂饮食。
保持线粒体健康的三个关键行动：
1. 健康饮食：富含水果、蔬菜和其他富含抗氧化剂的食物，帮助达到饱腹感而不至于热量超标。
2. 规律运动：包括正式锻炼和减少久坐时间。
3. 将自己视为需要规律活动的人：避免长时间静坐，中间穿插散步或简单活动。
视频结尾与信息汇总 (36:15 - 结尾)
Mario 感谢 Nick 的分享。
Nick 表示对话非常愉快。

</markdown>

Edit:2025.05.16<markdown>

This video is a conversation with Dr.

Nicholas Vhovven of the YouTube channel

Physionic about mitochondria and

specifically mitochondrial dysfunction.

Mitochondrial dysfunction is a common

cellular feature of most chronic

diseases. We see it in insulin resistant

liver and muscle cells and pancreatic

beta cells that are unable to secrete

enough insulin. And it therefore stands

to reason that mitochondrial dysfunction

is a key cellular process involved in

the development of type 2 diabetes.

But you can basically look up any

chronic disease from heart disease to

cancer to neurodeenerative diseases.

Mitochondrial dysfunction seems to be a

common denominator playing a role in all

of these conditions to some degree. So

with Nick, I specifically focused on

what we can do personally to keep our

mitochondria healthy and happy. Enjoy.

[Music]

Nick. So, welcome to Nerf Best by

Science on YouTube. Really glad to have

you here on uh the channel with us.

Yeah, sure. So, first of all, it's an

honor for me to be here. Um I consider I

I've told you this off platform, but you

are one of my top three sources of

nutrition and science information. So,

it really is an honor for me to be here.

Maybe we'll start slow and get into, you

know, what are mitochondria? What's

their basic function and why are they

important for our health?

Yeah, sure. So, mitochondria are an

organel. So, you everybody the the

viewer listener probably knows that we

have cells where our body is made of

billions and billions and billions of

cells. And most of those cells, not all

of them, but most of those cells have

organels. And the organels are just

these different structures within your

cells that serve particular functions

for the cell. Um, you can think of them

like, I don't know, factories and and

different systems within the cell. And

mitochondria are one of those systems.

So, they're one of these organels. And

in terms of their function, I mean, I

guess we might as well get this one out

of the way. Uh, it's the powerhouse of

the cell. I guess we can go ahead and

and mention that.

close the podcast. I think we're done.

Um, so that's that's something that pops

into people's minds often because it

gets kind of drilled into us from like

middle school into high school and then

of course beyond that as well that

mitochondria are the powerhouse of the

cell. So that means that they

essentially generate cellular energy for

for the cell. Now that said, uh they're

important in more than just that one

function, although that's what they're

most well known for and that's probably

what they'll be well known for for the

rest of our ex biological existence.

However, uh they mitochondria have other

functions as well. For example, cell

signaling.

So mitochondria have the ability to

communicate with the other organels and

the the enzymes and the different

proteins, functional proteins that are

found within the cell to allow the cell

to function. So it's not just cellular

energy that they generate. They also

generate other compounds. Uh they can

sequester or take up different

compounds, different molecules,

different ions. um they can they can

create balance within the cell. Um they

have a critical role in uh biosynthesis.

So they can actually generate new

molecules that can then be uh used for

like hormonal production. So like

cortisol, testosterone, estrogen, those

are all uh dependent on

mitochondria. And they also protect us

from cancer. So there's a really

powerful mechanism that when your cells

become defunct and they ultimately start

becoming cancerous and start giving this

uh this rise to cancer. Uh mito well

your cells have an independent mechanism

to to kill themselves to essentially

spare you from starting to develop

cancer. But uh mitochondria also have

this uh powerful system that works

through uh different uh different

triggers but ultimately leads to the

same fate that the the cell ends up

succumbing and and dying off just so

that it doesn't become cancer. So

there's a whole host of different ways

and that's certainly not an all

exhaustive list for why mitochondria are

important. One question I hear a lot is

people say oh you know so they just make

energy. So in other words, if my

mitochondria don't work well, I feel

like sluggish or weak. And they assume

that is because you know the

mitochondria don't make enough energy

for muscle movement. And there may be

something to it. But the other thing

certainly is that

um the energy that the chemical form of

energy produced in the mitochondria

plays a major role in also

um providing energy for all other

cellular processes. Right? So all other

transport mechanisms in the cell,

enzyatic activities, you know, just

converting DNA to proteins, all of these

processes require uh energy. And so a

lack of functional mitochondria can lead

to a deficiency in energy for all of

these processes, right? Not just muscle

contraction, which is what most people

may be associated with energy uh that

they need for the body.

Now an important term that people come

across there is this term uh

mitochondrial dysfunction. So

basically for some reason the

mitochondria stop working properly. Can

can you explain uh what we mean when we

say um oh you know researcher may look

at say the liver or a muscle cell and

may say say oh we observed signs of

mitochondrial dysfunction like what do

they mean with this?

Yeah. So there's a a number of different

layers to this. So I'll go through three

layers. Uh the top layer is just

mitochondria aren't functioning within a

normal range. So we'll just say that's

just kind of a a real basic definition

for mitochondrial dysfunction. A layer

under that which relates to how

researchers might assess it is they

might look at particular markers of how

mitochondria function. So we can

actually go back to some of the ones

that we were talking about in terms of

the importance of mitochondria because

some of those can be quantified pretty

easily. So we can look at for example

oxygen consumption by mitochondria

because to generate energy I won't go

into the biochemistry but to generate

energy. Mitochondria need to be taking

up oxygen. So what I mean that is the

primary reason why we take up oxygen is

so that they can be delivered to

mitochondria and then can go through

this biochemical process that ultimately

leads to cellular energy. So one way to

measure is by looking at uh isolating

mitochondria and then or even on a

cellular scale but usually we isolate

mitochondria and then we look at their

oxygen consumption rate. So that gives

you one indication of their health. If

it's high, well, that's typically a sign

that okay, it's it's uh functioning

well, but then you probably need to look

at some other indices as well, uh which

we can certainly get into. Another

metric that uh researchers might look at

is ATP generation, which is a little bit

more direct uh metric. Instead of just

looking at oxygen consumption, they

might look at ATP, which is uh if we

haven't mentioned it yet, ATP is the the

major cellular currency of the cell. uh

the the cell actually uses other

currencies as well, other uh energy

molecules, but ATP or adenosine

triphosphate is the the major one. So

those are two ways that researchers can

probe mitochondrial dysfunction. Then if

we were to go to a third layer, there's

there's a lot of different ways that

mitochondria can become dysfunctional

that are not related to energy. Uh so

the loss of the inability to to generate

cellular energy is definitely one of

them. However, mitochondrial dysfunction

can can come about due to a whole host

of different reasons. So uh another one

might be the loss of the membrane

potential. So to explain that a little

bit, your mitochondria have two

membranes. Uh they're they're kind of

like this double insulated organel. So

there's an outer membrane and an inner

membrane. And then on the very deepest

inside recesses of the mitochondria

called the matrix, you have in that

region, it's much more negative than the

outside of the mitochondria. So, we're

still inside the cell, but the inside of

the cell is more positive relative to

the very deepest region of the inside of

the mitochondria. Just keep in mind the

very deep inside part of the

mitochondria is supposed to be very

negative relative to the to the outside

of the mitochondria. Now, if there's an

imbalance, if you start to have more

positivity on the inside of the

mitochondria, the mitochondrian

basically shuts off. I mean, there's

there's no way for it to function

anymore. And from that point on it can

actually typically start going into uh

mitochondrial death. So it'll

essentially get destroyed. Uh and

typically that goes by uh the process of

autophagy. So autophagy of mitochondria

called mphagy. Uh researchers get really

creative with their names which is which

is great. So defective this defective or

loss of a membrane potential. So the

membrane potential is simply the

difference between the inside of the

mitochondrian and the outside of the

mitochondria. If you you lose that that

is a sign of mitochondrial dysfunction.

Defective mphagy is another sign of

mitochondrial dysfunction where the you

might see a loss in the mitochondrial

membrane potential but it does not

recruit the the the autophagy machinery.

I won't go into all the different names

of that, but the autophagy machinery

would then come by and be primed. Oh,

not that they're thinking about this,

but biochemically it gets targeted to a

mitochondrian that's lost its membrane

potential and then it engulfves it and

starts going through this process of

destroying it. So, you can get defective

mphagy as well. You can also get the

acrruel of different proteins on and

inside the mitochondria.

uh one example we actually our lab uh

that I did my PhD in we actually

released a review where we looked at

proteiotoxicity so it's essentially the

overaccumulation of different proteins

that are found on the outer membrane of

the mitochondrian but they can also find

them their way into the matrix of the

mitochondrian and if you have a bunch of

dysfunctional proteins that are either

not supposed to be there they may be

misargeted so instead of going to

another region of the cell to fulfill

the function that they're supposed to

fulfill. They get they can get

misargeted to mitochondria and can

actually attach to the mitochondria.

From that point, all the functional

proteins that are on mitochondria may

not be able to interact as well as

they're supposed to or you may just get

an overwhelming number of different

proteins that just don't function

anymore. So the acrruel of these

different proteins called

proteiotoxicity can lead to severe

mitochondrial dysfunction as well. Uh

physical damage, mitochondrial damage

itself which can occur through like

excessive reactive oxygen specy

generation. So these are damaging

molecules or what can be damaging

molecules that can interact with

different uh sections of the

mitochondria and start ripping away at

the the kind of the chemical integrity

of the mitochondria. So if uh you have

excess levels of these uh these

molecules then you can get damage to the

mitochondria. I and I should be I'm I'm

being very careful here to say excess

amounts because mitochondria do generate

ROS Ross reactive oxygen species for

cell signaling as well. So it's not just

that oh you see a little bit of Ross and

then therefore mitochondria are somehow

abnormal. Um it's just if you get excess

levels called oxidative stress. Um a

lack of calcium buffering. I mean I

could keep going. There's there's

there's a lot of different ways that uh

mitochondrial mitochondria can become

dysfunctional. I don't you know I don't

want to keep going and going and going

but if you if you want to know more I

can certainly cover more. So uh no I

think this is actually really

interesting uh discussion of you know

all the things that can go wrong inside

of the mitochondria and inside of the

cell you know the molecular things that

can go wrong that can lead to

mitochondrial dysfunction um and I'd be

happy to chat more about this but maybe

the overarching question you know if we

take like two three steps back and ask

um you know what are the

um reasons why a person may develop

mitochondrial dysfunction in the cells

of certain tissues or maybe all around

the body. U like what do we know about

the factors that may trigger

mitochondrial dysfunction through maybe

and that's this is maybe how we can

revisit some of these cellular

intracellular mechanisms and through

which intracellular mechanisms do we

understand if we do how this happens.

Yeah, there's a there's a lot of

factors. I mean, some of them I I

mentioned, so like uh excess reactive

oxygen specy generation. Um genetics is

another one. Some people are born with

mitochondrial

uh dysfunction that can be kind of on a

scale. So some people can have severe

levels where uh they may not physically

develop the way that they're supposed to

or you can have more minor versions

which uh can manifest in particular

situations. And uh I've spoken to people

that have reached out to me that have

been diagnosed with certain uh

mitochondrial disorders like MIOS is

one. Me L is is one. And it's I mean

they're they're not extremely common but

when they do happen I mean they do arise

specifically from uh from genetics. And

that's because you have like a loss of a

particular gene or you have a mutation

in a particular gene that ultimately

leads to uh the mitochondria not exactly

functioning the way it's supposed to. Uh

the other can we stay there for a

second? Would you would you mind

describing what the phenotype is of some

of these typical like genetic conditions

that lead to mitochondrial dysfunction?

Yeah. So usually the well it it very

much depends on which mitochondrial

disease you're talking about but you can

get for example an accumulation of fatty

acids. So for the viewer uh fatty acids

fat molecules like the ones that you

would consume from your nutrition or

that would be released from your fat

cells uh they can accumulate within the

cells that can ultimately lead to the

cell having all kinds of different

problems. And I know that you actually

release a lot of content on insulin

resistance. So that's a that's a major

uh way that that it can present itself.

Um other ways it can I mean it can

ultimately lead to apoptosis. So that's

cell death. So it's programmed cell

death. Uh so that can affect the organ

systems if that's like the liver or if

that's the brain, the eyes, the I mean

all kinds of tissues. I mean any any

tissue that has mitochondria are going

to be susceptible to to these different

conditions to varying degrees because

certain tissues uh rely on mitochondria

more than than other tissues. Uh and

there there are certain ways of you know

where metabolism is is very flexible but

again we we won't go down that that

road.

um in in genetics also Huntington's

disease if I could just quick mention

like a disease that people might be

aware of or Alzheimer's disease um you

can get an accumulation

of dysfunctional proteins that again can

accumulate on mitochondria so for

Huntington's we know that there's a

protein called

huntington huntington I believe it's

kind of like an extension of the the

Huntington disease

uh that accumulates on mitochondria and

stops mitochondria from being able to

function like they're supposed to or

with

Alzheimer's. And just to be clear, I'm

not saying that uh all disease is

related to to mitochondria. I'm also not

saying that Alzheimer's all comes down

to mitochondria. Um, I think if I could

just go off on a side note just for a

second, I think that when researchers

get interviewed about, you know, their

area of research, they start to start

attributing everything to to what they

study. Um, and I I'm not saying that,

but because there are, you know,

confirmed uh mechanisms by which

Alzheimer's is is caused, but

mitochondria because of some of the same

mechanisms are related to to these

different disease states. So that's a

that's a few examples. Okay. Yeah. Thank

you.

um maybe we we we could just take a look

at uh you know where I interrupted you

with the question if you know is there

something say that I could do or not do

that affects the health of my

mitochondria or could lead to

mitochondrial dysfunction and what do we

know about those dietary lifestyle

factors other exposures and how they act

through these mechanisms. So if we start

for example with excessive reactive

oxygen oxygen species

accumulation oxidative stress like what

do we know what kind of uh exposures

lifestyle factors that we can

potentially influence ourselves

uh can lead to oxidative stress and as a

result to mitochondrial dysfunction.

Yeah sure. So there are

th I'll name two major ones and then

there are some kind of I would call them

like uh tier

2 factors that influence that we that we

can influence that also influence uh

reactive oxygen specy uh generation or

over uh generation of reactive oxygen

species.

So actually let me to to really give you

to give the audience a a clear picture

of what we're talking about here. Let me

let me kind of paint a picture of the

structure of a particular section a

vital section of the mitochondrian and

then I'm going to

attack both problems that I'm going to

present in just a second uh through two

things that people can do. Um, so you

have a mitochondria and we've already

described how it has two membranes. Now

we're going to focus on the inner

membrane and in the inner membrane there

are these five proteins. Sometimes

researchers just focus on the four, but

there's five proteins that are embedded

or five major proteins that are embedded

into the inner membrane. And again, I'm

not going to go through all the

biochemistry of it, but the point being

that you have substrate delivery at one

point at one protein. And when I'm

talking about substrate delivery, I'm

talking about what comes from our

nutrition, what comes from our fat

cells, what comes from uh glucose in our

bloodstream. And I'm going to go into

that a little bit more in just a second,

but just for now, just know that

substrate for mitochondria to be able to

produce energy gets delivered to this

first protein. And then there's a chain

reaction, which is why it's called this

chain of proteins is called the electron

transport chain. is a chain reaction

that ultimately leads to the generation

of energy. Now, if the cell doesn't need

a whole lot of energy, but you have a

whole lot of substrate, then one of the

problems that can occur is you get

what's known as electron slippage, which

ultimately leads to the generation of

these reactive oxygen species at a

higher degree than what you'd normally

want. Think about that scenario and what

are two things that you could do that

could a reduce substrate and b create a

metabolic sync that rapidly sucks up a

lot of that ATP so that mitochondria do

have a place to to be able to generate

uh this this ATP and one is dietary

intake. So the and we can go into the

specifics of that dietary intake but the

biggest factor is overconumption. So if

you are over consuming in any way and

you're starting to gain weight that can

lead to a lot of this uh excessive

oxidative stress which ultimately

contributes to a whole host of different

disease states. But on the the far side,

so sucking up ATP, the best way to suck

up ATP is I mean we can focus on muscle.

Certainly exercise is a is a massive

metabolic sync as in it just takes up so

much ATP. As a matter of fact, I

remember in one of my courses in my

master's program, in one of my

bioenergetics courses, the the professor

said that typically we consume or or go

through about 40 kilograms of ATP per

day. But when you exercise, I I don't

know the exact amount of exercise. I

think he would he it was like a whole

lot. It was like a marathon or something

like that. You double that. So you go

through 80 kilograms of ATP. So now

imagine applying that to all your cells.

I mean that's such a huge demand for for

energy that it just it it liberates in a

in a kind of common term. It liberates

mitochondria to be able to use up so

much substrate and ultimately divert

that towards ATP production and far less

of it gets diverted to reactive oxygen

specy production. Um again and just as a

reminder for the viewer it's not like

the cells are thinking about this as

merely just reactions happening. I'm

sort of describing it like oh

mitochondria are deciding to put it one

way or another but that's not really

what happens within the cell. It's a lot

of reactions that are going on. So those

are the two big ones and then obviously

we can go into more detail on some of

the others. So

to to to clarify this for the viewer uh

and and connect it to some videos that

I've made

um when we overeat calories chronically

what happens is that the body tries to

store those calories initially in the

subcutaneous fat tissue that's all

around the body. Right? So everywhere we

have subcutaneous fat tissue and that's

really the only really safe uh tissue to

store fat long term. The problem is if

we keep gaining weight at some point the

subcutaneous fat tissue will be full.

Yeah. It will be unable to expand

further and store more. And what happens

then is that the body is forced to store

any extra calories that come into the

body in other tissues. And so the fat

that we consume or the carbohydrates we

consume that are being converted to fat,

they eventually find their way into

depot that are not primarily made for

long-term fat storage like the visceral

fat depot in the abdominal cavity. So

all around the inner organs and also

what we call ectopic fat storage. So

that is fat storage in organs that are

not at all made for fat storage. So good

examples here are the musculature

um and organs like the pancreas or the

liver specifically. And so what you're

what you're describing is that once we

have reached the point where we're no

longer able to store fat in the

subcutaneous tissue, which is often

referred to as crossing our personal fat

threshold. So if we've crossed our

personal fat threshold, we're no longer

able to store fat effectively or

efficiently in the subcutaneous fat

tissue. fat molecules start to

accumulate in different um tissues like

the liver like in muscle cells and then

they basically can become too much

substrate right for this process that

you're describing if I understand you

correctly and that can lead to um an

impairment in the normal functioning of

the mitochondria such that it can lead

to increased production of reactive

oxygen species and what we commonly

refer to as oxidative stress. Yes.

subscribe described that correctly.

Yeah, it was perfect. I wanted to

clarify this uh partly because my next

question is directly linked to this and

that is do we have any evidence to say

that it is actually this way that it

works that basically we do start to

accumulate say fat in muscle tissues.

Let's just stay with muscle tissue for a

second. We do start to accumulate fat in

muscle tissue because the fat has

nowhere else to go in the body. cannot

be safely stored in the subcutaneous

tissue anymore. But we keep eating and

so the fat finds its way into muscle

cells and now accumulates there and that

is what causes the mitochondrial

dysfunction and the increased excessive

production of reactive oxygen

species or do we have also evidence to

suggest that the dysfunctional

mitochondria could be there in the first

place and that contributes to an

excessive accumulation of fat in the

muscle cells. What's your view on this?

Probably depends on the disease state or

the particular circumstance. Sometimes

uh mitochondria may be affected by this

overaccumulation of nutrients and other

times it's because you have these

defunct mitochondria that you have uh

this accumulation of of nutrients. Let

me actually talk about one study though

that I I remember reading years ago

where they took perfectly normal uh

mitochondria, healthy mitochondria and

they applied this is one of the points

that I was going to talk about uh in

relation to diet. They applied different

types of fat. So the same level of fat,

same amount of fat but different types

of fat. And they were able to show that

for certain types of fat, which were

unsaturated fats, uh there tended to be

uh good outcomes for mitochondria as in

mitochondria would behave in a

particular way. And what I mean by

behave that mitochondria have the the

ability to change their shape rather

really drastically from very linear and

organized to extremely

fragmented. Um but when they added a

particular type of saturated fat and I

just want to be clear here that there

are many different types of saturated

fat for those listening u but the most

prevalent the most prominent is

palmatate. So that's why they chose

palmatate to to apply to the cells and

that did that itself as in mitochondria

were perfectly normal. Once they applied

palmatate at the same level again

suddenly mitochondria started massively

producing oxidative stress uh a lot of

different stress enzymes were activated

um and the cells ultimately were succumb

to to that injury and ended up dying. So

right there is at least some proof that

it is the nutrition or the the the I

guess I should say molecules that

specifically affect mitochondria and

cause this this damage. But again I just

I don't want to say oh it's definitely

that and it could never be anything

else. I should be open to to the

possibility that could be reversed as

well.

I actually really liked what you said

there uh that you felt that there is

good evidence to suggest

that you know even someone who has

perfectly good mitochondria let's say in

their musculature or in their liver

um that if they cross the personal fat

threshold and they're unable to store

fat safely in their subcutaneous depot

the fat finds its way into other

tissues. So suddenly fatty acids start

to arrive in muscle cells, they start to

arrive in liver cells. That that

accumulation of excessive substrate,

right, excessive fatty acids, may maybe

also excessive glucose can in and of

itself lead to mitochondrial

dysfunction, but that it could also be

that other factors cause the

mitochondrial dysfunction and that that

contributes or at least exacerbates the

accumulation of fat in the cell. Right?

Is that what I'm do I summarize that

correctly? Yeah, definitely.

um in this context I would actually like

to stick with this topic a little bit

because it's very fascinating uh in

terms of u one thing we haven't really

talked about and that is tissue

specificity and that what I mean with

this is that let's say if we look at a

fat cell a fat cell very obviously is

well equipped to handle a lot of fat

right so cell a subcutaneous fat cell

for anyone who's ever looked at these

under a microscope you know you have uh

let's say another cell type, let's say a

macrofase, just a cell type of the

immune system, you know, it's like a

tiny cell. And then a fat cell would by

comparison have this type of size,

right? So they're huge compared to most

other cell types. And they're filled,

you know, seemingly till they're could

burst with just one huge fat droplet,

you know, in the form of triglyceride,

similar to the form of fat, say in in

butter.

So very obviously in it does seem that

in the fat cell this huge accumulation

of fat doesn't lead to mitochondrial

dysfunction but much smaller amounts of

fat say in a muscle cell or liver cell

can wreck a lot of havoc including on

their mitochondria. Um can you comment

on that?

Yeah, actually I've got a great

example of mitochondria's relationship

to fat in uh muscle that is quite

different from well actually ties into

some of the things that you were saying

earlier about ectopic fat as well. So

there are examples

of lipid droplets. So these these kind

of sacks containing all these different

fats within them uh in muscle as well.

And for highly trained individuals, so

people who exercise quite a lot, they're

actually starts to develop some of these

lipid droplets within the musculature.

However, the relationship to

mitochondria is fascinating because the

the placement of these lipid

droplets is uh what's known as

myofibrillar. So, I'm not going to go

too into depth with that because I don't

want to lose lose people with some of

the technicalities, but the the point

being that it's it's kind of in the

deeper recesses of the cell and the

location of mitochondria right next to

the lipid droplets. And the belief is

that the reason why this happens is so

that the lipid droplets can can deliver

or somehow that these fatty acids and

these uh these fat molecules can be

delivered to mitochondria in such close

proximity. On the other hand, for

individuals who are uh severely

diabetic, people who uh might be obese,

uh they tend to have in the same exact

tissue, so muscle tissue, muscle cells,

they can also have lipid droplets that

start to accumulate, which is kind of

relating to the ectopic fat, but they

tend to be uh on the surface of the cell

and tend to be related to far more

insulin resistance.

So the exact same phenomenon happens but

simply because of the location of the

fat and the relationship to mitochondria

we're seeing completely different

scenarios uh between those two

conditions which I when I first ran

across that that research I just found

it absolutely fascinating uh that that

you can have that difference and then

once you start speaking about like fat

cells to your point about this one

massive lipid droplet uh and the

relationship I mean there's just so much

complexity there of well, why aren't

mitochondria in those fat cells? And of

course, you get into fat cell subtypes

like Beijing of fat and and the brown

fat and and you know, brown fat

obviously has this this tremendous

relationship with mitochondria that

white fat doesn't. It's just it gets so

complex. But the point being that

there's a lot of uh a lot of discovery

to to be had there in terms of why

mitochondria react certain ways to to

to the context of the cell that they're

in and the context of the fat that's

around the mitochondria.

And so is it your impression that say in

the case of an endurance runner this is

a carefully orchestrated process where

the cell actually notices oh repeatedly

we have demand for a lot of energy and

so we'll just create a planned store of

a little fat droplet inside the cell

next to the mitochondria. Whereas in

someone who's developing insulin

resistance and diabetes who just over

consumes calories, it's more of an

accidental deposition that just happens

and that the cell is forced to deal with

whether it wants it or not. Is that

maybe a fair way to kind of think about

this? Yeah, that's that's how I think

about it. Uh I mean obviously you'd have

to talk to a researcher that

specifically studies exactly those

phenomenon but my impression is that's

exactly right that uh although you know

a marathon runner or a endurance athlete

they they typically don't have a ton of

fat on them and what fat is there that

gets released from the fat cells has a

long way to go just to get to the

musculature. So the cells end up

developing these lipid droplets that are

in extremely close proximity with

mitochondria. On the flip side with

individuals who suffer from

obesity, the the fat depots, I don't

know if you've looked at some of the

literature on on the exchange of fat in

in the fat cells and around the fat

cells, but there's this massive exchange

that's like way above normal where it's

almost like the fat cells simply can't

hold on to the fat and just starts like

regurgitating it back out. And there's

some fascinating literature with immune

cells as well where immune cells will

start to crowd around the fat cells and

will start taking up the fat. Now, what

they're doing with that fat, I don't

know, but my hypothesis, not that I'm

ever going to test this, but my

hypothesis is that the immune cells are

trying to help oxidize some of those

fats, which if that turns out to be

true, would be incredibly cool, this

symbiotic relationship. But the point

being that with uh with people that

suffer from obesity, they they tend to

have higher triglyceride levels in their

bloodstream, which tends to then it

could accumulate in into the musculature

and all these other lean tissues. And I

wouldn't I wouldn't be surprised if that

happened in other lean tissues as well.

It doesn't necessarily have to be

muscle, but that's that's at least what

I've looked up. Yeah.

so let's maybe think about the second

part of the equation that you went into

and that is um the use of the ATP. So if

we let's say we have a muscle there's

some fat accumulating there and we start

to exercise even if just going for a

long walk every day right what happens

is the musculature needs more you know

these muscle cells need to generate more

ATP and so what what if I understood you

correctly one of the positive effects of

that is that it just starts to uh burn

up more of the accumulate accumulated

substrate like the glucose the fatty

acids in a way that is less likely to

lead to excessive reactive oxygen

species generation. Yes. Is that proper

summary? Yes. Yes. But there's some

additional benefits of exercise that are

not found from the previous part of that

equation looking at

nutrition. Uh or at least not heav not

as heavily I should say. Um exercise

also has this potent effect of because

it's so demanding on the energy supply.

Just as a quick biochemistry uh lesson

if you want to call it ATP gets changed

I'm just going to use kind of general

terms but changed to ADP. So adenosine

diphosphate. So triphosphate means that

it's got three phosphates then

diphosphate two phosphates and then it

can actually be further converted into

so mono phosphate. a single phosphate

that that dramatic drop from ATP to ADP

and then even from ADP to AM is a

massive cellular signal which ultimately

affects a protein that a lot of people

are pretty familiar with at this point

because there's a lot of uh hub about

autophagy which

ismpk is this protein that it can

actually be bound. The reason why it's

called

AMK is because AM these molecules that

start to build up due to exercise

because you're just using up such high

amounts of ATP and producing ADP which

again can get can can get converted to

uh AM although it can also be uh turned

back into ATP but that's a different

story. The point being that as AMP

levels rise and ADP levels rise, that

can activate EMPK, AMPK then has a

tremendous

impact on uh another protein called PGC1

alpha. PGC1 alpha and I promise I I'll

stop spitting out different protein

names, but the point being that PGC1

alpha is a is a mitochondria biogenesis

factor. It's the most potent one. So

this this protein which is highly

stimulated from exercise can then

activate mitochondria to start

generating more mitochondria. So,

because you're essentially creating this

quick stressor, and I mean quick by 30

minutes, an hour, a few hours of

exercise relative to your 24-hour day,

that that quick exposure to this stress

of a sudden drop in in ATP and a and a

and a significant increase in ADP and

AMP leads to mitochondria or the cell

starting to produce more mitochondria,

which ultimately bolsters the ability

for the cell to then be able to produce

that ATP and handle the next bout better

and then the next bout better and so on

and so forth. So it has this additive

effect that that exercise has that

nutrition doesn't quite have.

Yeah, thank you for that. So to recap

this part is um one thing that is I'd

say pretty clear is that if people

chronically over consume calories once

they cross their personal fat threshold

the glucose the fatty acids accumulate

in other tissues like the mus muscle

cells the pancreas cells the cells of

the liver probably others the brain is I

think a hot candidate for this as well

right um so there are then is then this

consequence that the mitochondria cannot

quickly enough um metabolize all of this

fat which immediately has been linked um

to insulin resistance in these tissues.

But in addition to that, the increased

availability of substrate in the cell

seems to contribute to mitochondrial

dysfunction partly through an increase

in excessive reactive oxygen species

generation.

So the conclusion there obviously would

be um try to eat in a way that uh

doesn't lead to chronic overconumption

of calories. Right? So I think that's

probably one of the most important

things anyone can do for their health is

to eat in a way that uh it doesn't

exceed their um total energy expenditure

and ideally if they have excessive fat

beyond their personal fat threshold they

should do whatever it takes to get rid

of that. The second part is uh exercise

which increases demand for ATP through

the mitochondria and also makes it makes

the mitochondria run more smooth simply

because it creates a tremendous pull for

ATP in a way that also reduces excessive

reactive oxygen species generation and

basically contributes to keeping the

existing mitochondria healthy while also

providing a stimulus through the use of

ATP to generate new ATP new

mitochondria. So in other words, if you

exercise regularly, the mitochondria uh

the number of mitochondria in your

muscle cells uh is it going to increase,

right? Is that correct? Yeah,

absolutely. And it'll increase

tremendously actually. So if we close

close that loop for a second because you

started at the beginning by saying that

uh in a cell culture dish you can test

the function uh of your mitochondria and

detect potential dysfunction by looking

at the rate of oxygen consumption.

We have a tester like this for the whole

human right the whole organismal level

where you can go into lab and measure

your V2

max that way right way to think about

this that if we regularly

uh keep our you know have lifestyles

that keep our mitochondria healthy and

exercise such that we actually increase

the number of mitochondria that that is

the mechanism through which we also

increase our V2 max.

Yeah exactly. So, I think of uh V2 max

as kind of this human proxy for

mitochondria, but I want to be clear

that it doesn't necessarily just

represent mitochondria because you could

have a low V2 max. Uh that is not

because of defunct mitochondria, but

because of something else. You may have

a pulmonary issue, you may have a

cardiovascular issue or something along

those lines. So, I don't want to say

that it's a one:one ratio. V2 max

immediately talks to to mitochondria.

But assuming everything else is

relatively healthy, it does I mean

you're literally consuming oxygen so

that it can del can be delivered to red

blood cells so that it can be delivered

to all these tissues so that that can

then be pushed into uh mitochondria for

energy generation. So absolutely there's

a there's a clear relationship there.

Yes. Um yeah, thank you for clarifying

that. I think that's it's really

fascinating to think about it this way,

right? So, if you have a high V2 max,

that simply means your entire system

works well, right? Your respiratory

system works well to get the oxygen into

you. Uh and get rid of the CO2. Uh that

your cardiovascular system works well to

transport the oxygen around the body and

your musculature works well in using the

oxygen. And that is what happens in the

mitochondria to generate the energy

that's needed for the exercise. Um so

let's maybe move on where you know we've

discussed

that excessive accumulation of substrate

in the cell or too low a demand because

we're just sedentary all the time can

lead to mitochondrial dysfunction. Now

there's several other factors that I

think have been linked to mitochondrial

health and I wanted to get your opinion

on some of those. So for example uh in

my last two videos I spoke about light

and this whole new area of near infrared

light potentially directing acting on

mitochondria and I also spoke about uh

cacao dark chocolate as a source of

polyphenols that seem to have

potentially

um antioxidative properties that may be

linked to improved mitochondrial

function. And there are certainly many

other examples like that where certain

exposures we may have good or bad could

either uh help us keep our mitochondria

working properly or that in and of

themselves could uh lead to

mitochondrial dysfunction. You've

mentioned earlier already certain fatty

acids like palmitic acid if they

accumulate within the cell they might by

themselves contribute to mitochondrial

dysfunction.

Um, can you think of what do you think

first of all of of like how do you think

about these types of factors in the

grand scheme of things and and do you

have other examples?

Yeah. So, I was going to bring up some

of these. I I hadn't intended to bring

up the the red light or near infrared

light, but uh it is an area that I've

looked at as well. Um, I'm always a

little dubious about those studies

because it's it's incredibly difficult

to have proper controls for that kind of

study. But, uh, you know, putting that

aside, uh, there are a number of studies

that have shown that the effect that red

light or near infr near infrared light

has on mitochondria and does seem to

improve the efficiency of mitochondria.

uh there's I think the mechanisms are

still a little bit being worked out. I

know that it affects some of those uh

some of those five proteins that I

mentioned in the inner membrane. It

seems to directly affect some of those.

Uh however, also there's something

called retrograde signaling from

mitochondria. So the just like I was

talking about with uh the changes in ATP

level from exercise that is sensed by

the entire cell. It's not just that it

affects, it affects all kinds of

different aspects of the cell. So, red

light seems to have an effect on that

kind of signaling. So, the exchange of

these different uh molecules within the

cell and in terms of polyphenols and

really just uh fruits and vegetables and

anything that has that's abundant in

antioxidants, that tends to be a benefit

for mitochondria.

More specifically, if uh other aspects

are leading

to let's say more oxidative stress, then

these antioxidants can come in and uh

affect

mitochondri almost think of it like a

burn can quiet the burn that's occurring

um due to uh this oxidative stress. I

will say also exercise just as a

speaking to exercise another benefit of

exercise is that it can stimulate

mitochondria to stimulate the production

of internal uh antioxidant systems as

well uh through the these reactive

oxygen species. Uh in terms

of other things that come to mind, I had

exercise, gaining weight as in uh you

would want to avoid that. An

antioxidant-rich diet is something that

a person would want. And then there's uh

a reduction in palmitatebased saturated

fats. That was another one. And also

something

that I don't I don't think I've ever

heard anybody else talking about this.

Not that this is like some massive

revelation, but taking care of other

systems within your body. What I'm

talking about is your cardiovascular

system. Something that can damage

mitochondria is the excess of oxygen or

the lack of oxygen in particular

situations. So when we're talking about

like atherosclerosis for example when

there's a coronary artery that gets uh

that gets oluded that gets blocked up

and you have a lack of blood flow which

means that you also have a lack of

oxygen delivery to downstream areas of

of the

heart those

cells have a sudden drop in uh oxygen

delivery which means that mitochondria

have no way of producing uh energy.

However, one thing that we found in re

in in the research literature is that if

you suddenly open that occlusion and

just allow all the blood flow back

through that area, that can lead to

what's known as reperfusion injury. And

one of the main reasons is that

mitochondria get suddenly flooded with

all these oxygen molecules that

ultimately lead to a mass spike in

reactive oxygen species. So, I know

that's an incredibly specific scenario,

but the overall takeaway there is that

improving your atherosclerosis risk and

just making sure that you overall uh try

to avoid those kinds of uh different

coronary issues uh is a great way to

also maintain mitochondrial health. And

it just turns out that a lot of the

things that you would do for that also

just directly affect mitochondria and

improve mitochondrial health. So one

thing that I was wondering about is um

if we develop mitochondrial dysfunction

in different diseases like if we look at

the literature right we'll find evidence

say in

um in pancreatic beta cells for example

that are unable to produce enough

insulin we'll find evidence there of

mitochondrial dysfunction in insulin

resistant liver cells and muscle cells

we'll find evidence of mitochondrial

dysfunction but also in let's say um you

know certain brain regions

In neurode degenerative diseases, we may

find evidence of mitochondrial

dysfunction. And so the question is are

all sorts of mitochondrial dysfunction

the same or does it and it just matters

which tissue is affected and then that

tissue basically gets sick or do we have

good understanding of like tissue

specific types of mitochondrial

dysfunction like how can we think about

that?

Yeah, my and this is uh educated

speculation just to be clear uh because

I have not looked at like the I haven't

related the different types of

mitochondrial dysfunction to specific

tissues or specific disease states

because it's usually talked about just

kind of as a as a overall uh definition.

Mitochondrial dysfunction is related to

Alzheimer's, diabetes, cancer, all these

different aspects. But my intuition is

that no, they they are very different um

from disease state to disease state uh

but also tissue when you're talking

about tissues as well. And I think the

best evidence of that would probably

come from some of the genetic studies

that have been done. Um if you're

looking I mean if you're I I can go back

to the Huntington uh example. That's a

particular type of

uh problem or mitochondrial dysfunction

that's related to the overaccumulation

of those proteins. Meanwhile, if you

were to look at obesity, it's probably

not necessarily or not in most cases

genetic related uh in terms of the

mitochondrial dysfunction, but more so

the over abundance of the the nutrients,

the substrate that's available or being

sedentary. uh would be another one

that's or you know insulin resistance is

also improved by exercise. So the lack

of exercise can also uh be be another

way that you get this uh dysfunction

because you have more reactive oxygen

species for example or you have fewer

mitochondria you have fewer healthy

mitochondria mphagy isn't as uh as

functional. So I would argue if if it

were just me kind of uh speculating on

this without looking at the research in

depth I would say that's probably

different from from one tissue to

another tissue. So if the viewers now

have become curious about their

mitochondria mitochondrial dysfunction

like is there any test they could have

done to figure out if they have

mitochondrial dysfunction or if not are

there certain indications that people

could use to at least get a sense of

what the state of their mitochondria is.

So there are tests uh some of them are

better than others. You'll have some

companies that will

do that will do tests where they just

kind of measure the

overall amount of mitochondrial proteins

like the five that I mentioned in the

inner membrane. I do not consider that

to be a good test of mitochondrial

function or dysfunction. Um it tells you

that you have a certain number of these

proteins but it doesn't really tell you

anything else. Um, however, I know the

Mayo Clinic, this is not something

that's like readily available. You'd

have to actually get a prescription or

or a consult with a physician that would

then uh say, “Okay, yeah, I've got you

slotted with the Mayo Clinic.” And then

they do a a huge gene array uh where

they and then they specifically target

these different mitochondrial genes that

they know are highly related to uh

mitochondrial diseases. and they can

also look and see if some of those are

mutated and then that would give you an

indication. Um beyond that I should also

say that and going back to your previous

point about the different uh tissues it

does depend on the tissue like you can

get a sample from let's say your skin or

fibroblasts or some or even muscle but

that doesn't necessarily speak to the

entire uh population of cells in in your

body and that's always al always been

the case. Um, if we kind of put that

argument aside, I don't think that there

are any like really readily available

ways to to measure mitochondrial

function or dysfunction. Um, aside from

we, you know, we did mention

uh V2. So, that is one way, but again,

that's not a onetoone relationship.

Uh beyond

that, I mean if you want to go to a lab,

if you want to volunteer, uh you you

could always volunteer uh and maybe some

researcher will do it for you. But uh I

just I in general it's it's just a very

difficult thing to measure just because

there's uh there's so many different

variables that you have to take into

account. Yeah. I I actually

um think this is also something that

holds research back actually right

because people who do intervention

research let's say you know I used to do

clinical intervention trials with

different dietary

exposures and um you know we didn't

measure mitochondrial function in muscle

or liver as an endpoint because it's

very hard to measure right so and that's

partly why

um you know the evidence we in in terms

of what the actual cause effect

relationship is like what happens first

for example what comes next is at this

point suboptimal right it's inconclusive

because we simply haven't done the

longitudinal studies with different

interventions where we know for sure

okay well this is the stance of the

mitochondria now and then we eat you

know whatever chocolate or broccoli or

uh eggs and this is what happens then to

them so I think that's to some degree um

you know a reason why some of this

research is based say on animal

experiments on cross-sectional studies

on u cell culture work and so forth and

there's certainly a lot still to learn

but I do hope that it has become clear

in this conversation to people that we

do already know quite a bit about it the

mitochondria are undoubtedly very

important for our normal function of our

all of our cells which means our entire

body.

Um, and the factors that we know about

for sure that keep our mitochondria

healthy are generally the factors that

we also understand are important for us

to be healthy, feel good, and minimize

our risk of chronic disease. Such as

overconumption of calories, chronic

consumption of over over chronic

overconumption of calories is definitely

a very bad thing for our mitochondrial

health.

lack of physical activity. So, chronic

sedentary behavior and just, you know,

never really uh exercising is a second

very bad factor for your

mitochondria. And a diet that's low in

antioxidants. So uh you know if we frame

this differently we would say the three

things you for sure can do to keep your

mitochondria healthy is make sure you

eat a healthy diet that is rich in

fruits and vegetables and you know other

antioxidant rich foods that helps you

eat to society without over consuming

calories and just think of yourself as

someone who needs to move regularly. be

that informal exercise sessions like

going for a run or doing resistance

training, but also just in terms of

minimizing sedentary time, right, where

we know for sure that if we sit for four

hours at a time, that's not a good

thing. And so maybe breaking it up and

going for a walk in between or just

doing a few squats, all of those are

almost certainly things that will be

beneficial for your mitochondria and as

a result for your metabolic and whole

body health in the long term, right?

Um, well, Nick, uh, I really appreciated

you taking the time for, uh, this

conversation. I, uh, thought this was

very interesting. Uh, and, uh, where can

people find you, learn more about you,

and connect with you? Well, it was a ton

of fun for me, too, considering I got to

talk most of the time. So, anytime a

scientist gets to talk about what they

love to talk about, uh, no complaints

there. Uh, also lovely company. But um

people can find me at physionic. So phy

ss io n i. So it's physio like

physiootherapist but just cut the

therapist and put NIC in there. Stick

them together and you got me. I'll show

up on Google. I'll show up on all the AI

models. I'll show up everywhere. So just

uh just look that up. Yeah. And I'll

leave a link to the excellent physionics

channel in the description box below

this video. So thanks so much again uh

for this conversation Nick. Yeah thank

you. That was my conversation with Dr.

Nicholas Vhovven of the YouTube channel

Physionic. I have left a link to his

channel in the description box below and

I very much recommend that you check it

out because Physionic is one of the few

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