#31 - Navdeep Chandel, Ph.D.: metabolism, mitochondria, and metformin in health and disease
In this episode, Nav Chandel, Professor of Medicine and Cell and Molecular Biology at Northwestern, discusses mitochondria's role beyond ATP production, exploring their function as signaling organelles. He challenges conventional views on antioxidants, metformin, and aging, and delves into the Warburg effect in cancer.
Deep Dive Analysis
19 Topic Outline
Nav Chandel's Journey to Mitochondria and Metabolism
Hans Krebs, TCA Cycle, and ATP Production Explained
Cytochrome C Release and Programmed Cell Death (Apoptosis)
Reactive Oxygen Species (ROS) as Signaling Molecules
The Dual Nature of Antioxidants: Helpful or Harmful?
Ferroptosis: A New Form of Cell Death
Mitochondrial DNA: Origin, Vulnerability, and Maternal Inheritance
Mitochondria as Signaling Organelles Beyond ATP
Mitochondrial Function and the Aging Process
Metformin: Mechanisms, Anti-Diabetic, Anti-Cancer, and Anti-Inflammatory Effects
Mitochondrial Complex One Inhibition and NAD/NADH Ratio
Metformin's Anti-Cancer Properties and the Warburg Effect
Targeting Mitochondria for Cancer Therapy
Somatic Mutations vs. Mitochondrial Dysfunction in Cancer
Revisiting Antioxidants and Vitamin C Benefits
NAD Precursors and Sirtuin Activity
MitoQ and Targeted Mitochondrial Antioxidants
Metabolite Toxicity as a Cause of Pathology
Cortisol, Stress, and Metabolic Health
8 Key Concepts
TCA Cycle (Krebs Cycle)
A circular series of enzymatic reactions occurring in the mitochondria that processes pyruvate (derived from glucose) into acetyl-CoA, generating reducing equivalents (NADH and FADH) for energy production and carbon backbones for biosynthesis.
Electron Transport Chain (ETC)
A system within the mitochondria that uses electrons from NADH and FADH to pump protons, creating an electrochemical gradient (like a battery). This gradient is then used to synthesize ATP, the cell's energy currency, with oxygen as the final electron acceptor.
Mitochondria as Signaling Organelles
Beyond their role as cellular powerhouses making ATP, mitochondria actively release molecules like reactive oxygen species (ROS), cytochrome C, and metabolites into the cytoplasm. These molecules act as signals to control various cellular functions, including cell death, immune responses, and gene expression.
Reactive Oxygen Species (ROS)
Molecules like superoxide and hydrogen peroxide, traditionally viewed as toxic byproducts of mitochondrial function. However, they are now understood to also serve as beneficial signaling molecules under physiological conditions, regulating processes like immune function and the adaptive response to exercise.
Apoptosis (Programmed Cell Death)
A highly regulated process of cell self-destruction. A key trigger is the release of cytochrome C from the mitochondria into the cytoplasm, initiating a cascade of proteolytic enzymes (caspases) that lead to the orderly dismantling of the cell.
Ferroptosis
A recently discovered form of regulated cell death distinct from apoptosis. It is characterized by iron-dependent lipid peroxidation, where hydrogen peroxide interacts with free iron and polyunsaturated fatty acids to create toxic lipid hydroperoxides, leading to cell demise.
Warburg Effect
An observation by Otto Warburg that cancer cells preferentially use glycolysis (glucose to lactate) even in the presence of oxygen, rather than oxidative phosphorylation. While initially thought to imply suppressed mitochondrial function, current understanding suggests mitochondria are still necessary for providing biomass for cancer cell growth.
Metabolite Toxicity
A proposed concept suggesting that certain metabolites, normally present at low levels, can accumulate to toxic concentrations and directly cause pathology. This is distinct from proteotoxicity (misfolded proteins) and is supported by observations in inborn errors of metabolism where specific metabolite imbalances lead to severe diseases.
8 Questions Answered
Historically, mitochondria were considered solely as the 'powerhouses' of the cell, primarily responsible for generating ATP. However, it's now understood they also act as crucial signaling organelles, releasing molecules that influence cell life, death, and function.
Not necessarily. While traditionally seen as beneficial for scavenging 'toxic' reactive oxygen species (ROS), high doses of antioxidants can paradoxically turn off beneficial physiological responses, such as those induced by exercise or necessary for immune function, as ROS can act as important signaling molecules.
Metformin acts as a weak inhibitor of mitochondrial complex one, part of the electron transport chain. This inhibition activates AMPK, signaling low energy, which in turn reduces glucose production in the liver and may contribute to its anti-inflammatory and anti-cancer properties.
Mitochondria retain a small, circular set of 37 genes (13 essential for respiration), a remnant of their bacterial origin. This mitochondrial DNA is highly vulnerable to damage due to its proximity to ROS and lack of robust repair mechanisms, yet it's critical for function and inherited maternally.
Yes, despite the 'Warburg effect' suggesting cancer cells rely on glycolysis, genetic experiments show that robust mitochondrial function, particularly TCA cycle activity, is necessary for tumorigenesis by providing essential building blocks for rapid cell proliferation.
Studies suggest that orally administered NAD precursors are largely taken up by the liver, where they are converted into NAD. While some downstream products may circulate, it's not clear if these supplements broadly increase NAD levels in all tissues or primarily impact the liver and potentially immune cells.
Cortisol is a crucial hormone involved in stress response and various metabolic functions. While essential, chronic hypercortisolemia (excessive cortisol) can be detrimental, potentially impacting blood pressure, melatonin secretion (and thus sleep/neuro-regeneration), and even causing damage to mitochondria.
Yes, but not primarily due to their antioxidant properties. For example, vitamin C from an orange is essential for certain enzymes that control DNA methylation and gene expression, ensuring proper cellular function, rather than just scavenging free radicals.
9 Actionable Insights
1. Prioritize Stress Response Management
Focus on controlling your response to stress, as chronic high cortisol can negatively impact blood pressure, sleep, neuro-regeneration, and mitochondrial function. Practices like meditation are valuable tools for stress regulation.
2. Reconsider Antioxidant Supplements
Avoid supplemental vitamin C, vitamin E, or proprietary antioxidant blends, as their benefits for human health appear negligible and some trials show worse outcomes, especially for cancer patients. High doses of antioxidants can also turn off beneficial genetic responses from exercise.
3. Avoid Mitochondrial Boosting Supplements
Do not take supplements aimed at boosting mitochondrial function for normal aging, as there is no evidence to support their benefit and mitochondrial function may not be rate-limiting in healthy individuals. A slight decline in mitochondrial function with age might even be adaptive.
4. Approach NAD Precursors with Caution
Be cautious with NAD precursor supplements (NR, NMN) as a significant portion may be taken up by the liver, and their widespread ‘magical properties’ in other tissues are not fully established. Consider their potential role as mild anti-inflammatory agents, especially in immune cells.
5. Metformin Use: Personal Context
If you are healthy and active, you may already be mimicking some of metformin’s beneficial effects, reducing the perceived need for the drug. A cautious approach is recommended, waiting for rigorous clinical trial data before use.
6. Consume Natural Vitamin C
Obtain Vitamin C from natural sources like one orange a day to support enzymes crucial for proper gene expression, rather than for its antioxidant properties or in high supplemental doses.
7. Implement Daily Fasting
Shift focus from precise macronutrient/micronutrient ratios to strategies involving prolonged caloric deprivation, such as incorporating a daily 15-hour fast for health optimization.
8. Mindful Alcohol Consumption
Weigh the known toxicity of ethanol (even at low doses) against potential emotional or social benefits, and avoid drinking merely for the sake of it, especially in low-enjoyment situations (e.g., airplane alcohol).
9. Read “Navigating Metabolism”
Read Navdeep Chandell’s book, “Navigating Metabolism,” to gain a comprehensive understanding of metabolism without needing to consult multiple advanced textbooks.
6 Key Quotes
Mitochondria as signaling organelles.
Nav Chandel
Mitochondrial function is necessary for tumorigenesis.
Nav Chandel
The Venn diagram where they all overlap is inflammation.
Nav Chandel
It's like a hen, it's like a hen house next to where the fox is like.
Nav Chandel
Correlation versus causality.
Peter Attia
You've got to be able to do successive blows to a vulnerable cell.
Peter Attia