December 3, 2018

Podcast

Navdeep Chandel, Ph.D.: metabolism, mitochondria, and metformin in health and disease (EP.31)

"I pay more attention today to stress than anything else." —Nav Chandel

by Peter Attia

Read Time 11 minutes

In this episode, Nav Chandel, a professor of medicine and cell and molecular biology at Northwestern University, discusses the role of mitochondria and metabolism in health and disease. Nav also provides insights into the mitochondria as signaling organelles, antioxidants, and metformin’s multifaceted effects on human health, among many topics related to well-being.

Subscribe on: APPLE PODCASTS | RSS | GOOGLE | OVERCAST | STITCHER

We discuss:

  • What got Nav interested in mitochondria [5:00];
  • Reactive oxygen species (ROS) [16:00];
  • Antioxidants: helpful or harmful? [20:00];
  • Mitochondria as signaling organelles [22:00];
  • Hydrogen peroxide (H2O2) [25:00];
  • Mitochondrial DNA [28:00];
  • Mitochondria and aging [45:00];
  • Metformin [52:45];
  • Metformin and the gut microbiome [54:00];
  • Metformin as complex I inhibitor and the importance of the NADH/NAD ratio [1:01:00];
  • Anticancer benefits of metformin [1:07:45];
  • Mitochondrial function is necessary for tumorigenesis [1:15:00];
  • Are somatic mutations the result of mitochondrial dysfunction? [1:31:30];
  • Vitamins and antioxidants [1:37:00];
  • Targeting inflammation in disease [1:43:00];
  • NAD precursors [1:45:45];
  • MitoQ [1:52:00];
  • Metabolite toxicity [1:56:30];
  • Cortisol and healthy aging [2:02:00];
  • Nav turns the tables and asks Peter how he deals with the “So what should I eat?” question during social encounters [2:09:00]; and
  • More.

Featured image credit: Richard Wheeler via visually

§

 

Show Notes

What got Nav interested in mitochondria [5:00];

  • Nav went from math to mitochondria
  • Math major in college
  • Worked in a transplant laboratory
  • Got interested in metabolism
  • Lots of math in mitochondria
  • Most influential for Nav was a 1996 paper by Xiaodong Wang and the findings on cytochrome c and apoptosis

1996 experiment by Xiaodong Wang about cytochrome c.: Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. (Liu, et al., 1996)

Reactive oxygen species (ROS) [16:00];

  • Mitochondrion releases superoxide and H2O2
  • Free radical leak is not just a byproduct
  • It can dictate and signal cellular function
  • Thought that signaling only happening when the cell isn’t working
  • But mitochondrial generation of H2O2 physiological
  • T cells and infections, H2O2 used to properly function

Figure 1. ROS regulation of normal and cancer cell proliferation. (A) H2O2 is required for activation of a number of cellular pathways involved in cellular growth, survival and proliferation and in metabolism and angiogenesis. (B) Cancer cells generate higher levels of ROS that are essential for tumorigenesis. Genetic alterations leading to activation of oncogenes (PI3K, MAP kinase, HIFs, NF-kB) and loss of tumor suppressors (p53) coordinate an elevated redox state. ROS is also generated by increased oxidative metabolism and hypoxia in rapidly expanding tumors. In addition, cancer cells express elevated levels of cellular antioxidants (SODs, GSH, GPx, and PRx), in part through NRF2, to protect against oxidative- stress-induced cell death. Image credit: Scheiber and Chandel, Current Biology, 2014

Antioxidants: helpful or harmful? [20:00];

  • If ROS were only toxic, antioxidants great
  • If they’re also there for immune function, antioxidants can blunt adaptive immunity, etc.
  • Sepsis (tons of inflammation and autoimmunity) and ICU: antioxidants made the situation worse
  • Vitamin E trials on cancer did not show a benefit, possible harm
  • Exercise and antioxidants experiment: take a biopsy and look at all of the genes that exercise turns on — we think they’re beneficial to the body — if you give high doses of antioxidants, it turns off that beneficial response (of turning those genes on)
  • Exercise triggers the transcription of genes that we think are beneficial – give high doses of antioxidants and it turns off the beneficial response
  • Mitochondria integrates stress and signals the cell accordingly, genes are upregulated by ROS, and now antioxidants are blunting this post-exercise

Mitochondria as signaling organelles [22:00];

  • All of Nav’s talk have this title
  • Under physiological conditions, mitochondria provides normal feedback, plays a signaling role
  • H2O2 is used by immune cells to properly function
  • Cytochrome C is another signal
  • A number of different way apoptosis is induced

Hydrogen peroxide (H2O2) [25:00];

  • H2O2 will signal for positive responses
  • Exercise
  • Immune function
  • But they can also cause cell death
  • Ferroptosis – lipid H2O2 – can be toxic – lipid, iron, and H2O2 can get together and trigger apoptosis
  • Enzymes are constantly mopping up ROS – probably 30 enzymes

Figure 2. ROS regulation of inflammation. (A) Activation of the innate immune system requires ROS signaling. Common patterns associated with pathogens or cell damage (PAMPs or DAMPs) activate surveillance receptors (TLR, NLR, RLR), which increase ROS through NAPDH oxidase (NOX) enzymes and mitochondria. ROS is required for the release of pro-inflammatory cytokines (IL-1b, TNFa, IFNb) to effect an appropriate immune response. (B) Low levels of ROS maintain a healthy immune system. Decreasing ROS levels inhibits activation of proper immune responses, leading to immunosuppression. Elevated ROS levels contribute to autoimmunity through increasing the release of proinflammatory cytokines and proliferation of specific subsets of adaptive immune cells. Image credit: Scheiber and Chandel, Current Biology, 2014

Mitochondrial DNA [28:00];

  • 37 genes, but 13 genes essential for the respiratory chain to work the ETC
  • The mitochondrial genome was originally coequal: 1,000s of mtDNAs and about 1,500 nDNA genes
  • The mitochondrial genome now retains:
    • 37 genes
    • 13 polypeptides
    • 22 tRNA
    • 2 ribosomal RNA (rRNA)
  • Most of the genes are now located in the nucleus, with 13 remaining in the mitochondria
  • If you’re going to put 2,000 genes in the nucleus, why keep 13 polypeptides in the mitochondria?
    • Complex I: 7 of the 45 proteins
    • Complex III: 1 of the 10 proteins
    • Complex IV: 3 of the 13 proteins
    • Complex V: 2 of the 17 proteins
  • Those polypeptides are the electron and proton carriers for those enzymes (Complexes I, III, IV, and V)

Figure 3. Human mitochondrial DNA with the 37 genes on their respective H- and L-strands. Image credit: Emmanuel Douzery

Mitochondria and aging [45:00];

  • The data suggests that as you age there’s a decrease in mtDNA
  • Some of that mitochondria also may have mutations (deletions) and the capacity to generate ATP is impaired
  • But Nav doesn’t think that this is necessarily rate limiting
  • When they knock out a protein in mitochondria to go from 100% capacity to 0%, pathology happens
  • But when they go from 100% to 50%, they don’t see pathology, even under stress
  • We probably use 20% capacity, on average
  • We might go up to 40-50% when sprinting

Metformin [52:45];

Nobody quite understands how metformin works

It has three effects

  1. Lower glucose production in the liver
  2. Anti-inflammatory effects
  3. Anticancer effects

Metformin is a weak complex I inhibitor: might activate stress responses that fight off disease

  • It’s possible that if you inhibit mitochondria, it can activate a variety of pathways, which can promote the antidiabetic, anti-inflammatory, and anticancer effects
  • Metformin seems to selectively target the liver, kidney, and gut
  • Metformin doesn’t get into the muscles much, the heart (probably a good thing)

Metformin and the gut microbiome [54:00];

  • Metformin may have beneficial effects on the gut microbiome
  • It could also have an effect on the immune cells
  • With metformin, aspirin, and statins, they all overlap on inflammation

Figure 4. Pyruvate to lactate conversion. Image credit: Namrata Chhabra, M.D.

Metformin as complex I inhibitor and the importance of the NADH/NAD ratio [1:01:00];

  • NADH to NAD ratio is going to be slowed down when taking metformin due to complex I inhibition
  • Lactate can eventually become glucose via gluconeogenesis, and that takes NAD
  • With metformin you don’t have as much NAD, this slows down and you don’t make as much glucose
  • The ratio of NADH to NAD may be more important than absolute levels of NAD
  • Most people say you need to boost your mitochondria
  • But how does that square with the data on metformin?
  • Nav’s group have engineered cells in mice to get rid of complex I and put back a yeast complex I which is refractory to metformin: it doesn’t pump protons
  • The battery is a little less charged

Figure 5. AMPK signaling pathway. Image credit: Cell Signaling Technology, Inc.

Figure 6. Metformin Inhibits Mitochondrial Glycerol-3-Phosphate Dehydrogenase (mGPD), Raising Cytosolic NADH and Blocking Incorporation of Lactate into Glucose. (A) If mGPD functions predominantly in the glycerophosphate shuttle (red box), inhibition by metformin will be expected to slow the removal of NADH, leading to an increase in the cytosolic NADH/NAD+ ratio that feeds back on lactate dehydrogenase (LDH). (B) If flux from glycerol to glucose is significant (blue box), inhibition of mGPD by metformin may lead to accumulation of glycerol-3-phosphate (G-3-P) such that oxidation to dihydroxyacetone phosphate (DHAP) by cGPD becomes favorable. Whereas mGPD catalyzes this reaction by donating electrons directly to the electron transport chain, cGPD would concomitantly produce NADH, increasing the cytosolic NADH/NAD+ ratio, which would feed back on LDH. Note that the glycerophosphate shuttle catalyzes the net transfer of electrons from NADH to ubiquinone (Q) in the electron transport chain with regeneration of the intermediate dihydroxyacetone phosphate (DHAP) and G-3-P pools. Reverse flux through cGPD would not be expected in the absence of an external source of G-3-P or oxidation of the cytosolic NADH pool. Image credit: Baur and Bimbaum, Cell Metabolism, 2014

Figure 7. Anabolic pathways that promote growth. Glucose metabolism generates glycolytic intermediates that can supply subsidiary pathways including the hexosamine pathway, PPP, and one-carbon metabolism, all of which support cell growth. Mitochondrial TCA cycle intermediates such as oxaloacetate (OAA) and citrate are used to generate cytosolic aspartate and acetyl-CoA for nucleotide and lipid synthesis, respectively. Mitochondria also generate H2O2 and acetyl-CoA for redox signaling and acetylation, respectively. NADPH is used to drive anabolic reactions and to maintain antioxidant capacity. Cytosolic sources of NADPH include the oxidative PPP, IDH1, and enzymes from one-carbon metabolism including MTHFD1. Mitochondrial sources of NADPH include MTHFD2, MTHF2L, and IDH2. HK2, hexokinase 2; G6PDH, glucose-6-phosphate dehydrogenase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LDH, lactate dehydrogenase; ACLY, ATP citrate lyase; GLS, glutaminase; SHMT, serine hydroxymethyltransferase; MTHFD2, methylenetetrahydrofolate dehydrogenase 2; MTHFD2L, MTHFD2-like; ACSS2, acyl-CoA synthetase short-chain family member 2; THF, tetrahydrofolate. Image credit: DeBarardinis and Chandel, Science Advances, 2016

Anticancer benefits of metformin [1:07:45];

  • Nav’s group reduced the tumor burden in mice by giving metformin
  • Thinks there is strong evidence for complex I inhibition providing the antidiabetic and anti-inflammatory benefits
  • Metformin caused the TCA cycle to slow down in tumors in humans

Figure 8. TCA cycle. Image credit: Wikipedia

Mitochondrial function is necessary for tumorigenesis [1:15:00];

  • Mitochondrial function is necessary for tumorigenesis
  • Nav’s group targeted mitochondria inhibition for cancer therapy

Paper proposing a different reason for the Warburg Effect: Understanding the Warburg effect: the metabolic requirements of cell proliferation (Vander Heiden et al., 2009) [1:17:45]

“A very elegant” review written by Nav on cancer metabolism: Fundamentals of cancer metabolism (DeBerardinis et al., 2016) [1:20:00]

Mitochondria necessary for tumorigenesis: Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity (Weinberg et al., 2010) [1:26:15]

Are somatic mutations the result of mitochondrial dysfunction? [1:31:30];

Nav believes the opposite: that mitochondrial dysfunction is the result of somatic mutations

Three contrarian points from Nav:

  1. Antioxidants: dietary ones, have no benefit for human health and disease
  2. Theory that ROS and oxidants are bad: that theory is wrong
  3. Glycolysis is necessary, but so are mitochondria

Vitamins and antioxidants [1:37:00];

  • There are benefits in eating an orange
  • There are enzymes that control DNA methylation and other reactions to maintain proper function and gene expression
  • Your genes turn on and off properly via enzymes that are dependent on vitamin C and you basically need about an orange a day

Targeting inflammation in disease [1:43:00];

  • Metformin may keep inflammation down and have long-term effects
  • One of Nav’s favorite trials: the CANTOS trial

Nav’s favorite trial about inflammation and cardiac disease: Interleukin-1 Beta as a Target for Atherosclerosis Therapy: Biological Basis of CANTOS and Beyond. (Libby P., 2017) [1:43:30]

  • Another trial looking at inflammation recently is using low-dose methotrexate (the CIRT trial)
  • The CIRT trial showed that low-dose methotrexate did not reduce IL-1β, IL-6, hsCRP, or CV events compared with placebo among patients with established CAD and either DM or metabolic syndrome or both

Study about low-dose methotrexate and cardiac events that was stopped early: Cardiovascular Inflammation Reduction Trial – CIRT | (acc.org) [1:43:55]

  • ROS can serve as signaling molecules to activate cytokines
  • Metformin, by inhibiting the respiratory chain, which is a major site of those reactive oxygen species, decreases reactive oxygen species and decreases cytokine production
  • Dampening it enough that if you get an infection you can still respond.
  • Just keeping the set point where you’re at a little bit lower and that may have some benefits when you add it up over decades

NAD precursors [1:45:45];

The argument is that NAD levels decline with age, and with that, you lose sirtuin activity

NAD and metformin may crosstalk in two places

  1. There may be some healthy metabolic effects of NAD precursors on the liver
  2. NAD precursors may get into immune cells

MitoQ [1:52:00];

  • MitoQ is basically CoQ10
  • MitoQ has a cation on it which increases its affinity to get into the mitochondria
  • Problem is the therapeutic window is very tight
  • Ubiquinol is the reduced form of CoQ10 which is an antioxidant
  • Probably low risk and low benefit in a supplement like MitoQ with a potential to interfere with normal ROS signaling

Metabolite toxicity [1:56:30];

  • What if there’s metabolite toxicity?
  • Metabolites that are normally found at low levels and perform normal functions can rise and incur pathology
  • Metabolites are at a certain threshold are sufficient to cause pathology based on inborn errors in metabolism
  • In Alzheimer’s, maybe particular metabolites that increase are leading to pathology
  • When NADH goes up and NAD goes down, L-2HG gets made

L-2HG: Hypoxia Induces Production of L-2-Hydroxyglutarate (Intlekofer et al., 2015) [1:57:30]

Cortisol and healthy aging [2:02:00];

  • Nav pays more attention to stress than anything else
  • If stress is somehow being metabolically manifested through cortisol to the mitochondria, it could play a very important role in health
  • Stress may be the hardest thing for most people to control

Nav turns the tables and asks Peter how he deals with the “So what should I eat?” question during social encounters [2:09:00];

  • There’s a lot of bias and limitations in diet studies
  • Peter does not have a lot of interest in mouse studies for human nutrition
  • Short term vs long term insulin resistance on a ketogenic diet and the difference between physiological and pathological insulin resistance important to take into context
  • Huge elevations of glucose and insulin when someone fasted or ketogenic first encounter a carbohydrate
  • Muscle is basically saying any glucose in the system we’re going to save for the brain since we have all the fatty acids and BOHB as a metabolic substrate when fasted or ketogenic
  • Peter is focused on fasting windows than sticking to one diet vs another
§

 

Selected Links / Related Material

Peter and Nav’s trip to Easter Island discussing mTOR/rapamycin: The Tim Ferriss Show: My Life Extension Pilgrimage to Easter Island | Tim Ferriss (tim.blog) [01:00]

Nav’s book from 2015: Navigating Metabolism by Navdeep Chandel | (amazon.com) [1:15, 59:00]

Per Nav, the three greatest discoveries in the field of mitochondria: [7:00]

Role for mROS in adaptive immune cell function as well as innate immune cell function: Physiological roles of mitochondrial reactive oxygen species (Sena and Chandel, 2012) [18:30]

Antioxidants and sepsis: Rethinking Antioxidants in the Intensive Care Unit (Jain and Chandel, 2013) [19:30]

Vitamin E and cancer trial: Selenium and Vitamin E Cancer Prevention Trial (SELECT): Questions and Answers | National Cancer Institute (cancer.gov) [19:30]

Exercise and antioxidants: Antioxidants prevent health-promoting effects of physical exercise in humans (Ristow et al., 2009) [20:30]

Ferroptosis, a newly discovered form of cell death: Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death (Dixon et al., 2012) [24:45]

Steve Fesik and promoting apoptosis in cancer cells: Promoting apoptosis as a strategy for cancer drug discovery (Fesik, 1995) [27:00]

Nobel Prize in Chemistry in 2003 to Peter Agre for discovering aquaporins: Peter Agre Biographical | (nobelprize.org) [40:30]

MitoQ is a mitochondrial rejuvenating supplement: MitoQ [49:15, 1:52:00]

Metformin was discovered by goats eating lilac in France: Metformin: History | (wikipedia.org) [51:30]

Metformin and gut microbiome: Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug (Wu et al., 2017) [54:00]

Peter’s favorite word: Autophagy | (wikipedia.org) [56:30]

Books on biochemistry: [59:45]

NAD paper by Josh Rabinowitz: Quantitative Analysis of NAD Synthesis-Breakdown Fluxes (Liu et. al, 2018) [1:02:00]

Nav’s experiment that showed metformin can reduce tumors in mice by inhibiting complex 1: Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. (Wheaton et al., 2014) [1:06:00]

Study showing metformin caused the TCA cycle to slow down in tumors in humans: Metformin Targets Central Carbon Metabolism and Reveals Mitochondrial Requirements in Human Cancers (Xiaojing et al., 2016) [1:10:45]

Paper proposing a different reason for the Warburg Effect: Understanding the Warburg effect: the metabolic requirements of cell proliferation (Vander Heiden et al., 2009) [1:17:45]

“A very elegant” review written by Nav on cancer metabolism: Fundamentals of cancer metabolism (DeBerardinis et al., 2016) [1:20:00]

Mitochondria necessary for tumorigenesis: Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity (Weinberg et al., 2010) [1:26:15]

MD Anderson papers discussing drugs targeting mitochondria: An inhibitor of oxidative phosphorylation exploits cancer vulnerability. (Molina et al., 2018) [1:27:00]

Phase 1 safety trial for drugs targeting TCA cycle enzymes for pancreatic cancer: Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial. (Alistar et al. 2017) [1:28:15]

Andrew Dillin’s work in worms showing longer lifespan by reducing complex 1 and 3: The Cell Non-Autonomous Nature of Electron Transport Chain-Mediated Longevity (Durieux et al., 2011) [1:33:30]

Nav’s favorite trial about inflammation and cardiac disease: Interleukin-1 Beta as a Target for Atherosclerosis Therapy: Biological Basis of CANTOS and Beyond. (Libby P., 2017) [1:43:30]

Study about low-dose methotrexate and cardiac events that was stopped early: Cardiovascular Inflammation Reduction Trial – CIRT | (acc.org) [1:43:55]

Paper showing NAD must be made in the cytoplasm, not in the mitochondria: Nicotinamide adenine dinucleotide is transported into mammalian mitochondria. (Davila et at., 2018) [1:46:15]

L-2HG: Hypoxia Induces Production of L-2-Hydroxyglutarate (Intlekofer et al., 2015) [1:57:30]

Global study suggesting no amount of alcohol is good for health: Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016 (Griswold et al., 2018) [2:08:15]

Mediterranean diet study: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet (Estruch et al., 2014) [2:13:15]

Macronutrient diet study: The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice (Solon-Biet et al., 2014) [2:16:45]

§

 

People Mentioned

§

 

Navdeep Chandel, Ph.D.

Navdeep S. Chandel is a Professor in the Department of Medicine and Cell Biology at Northwestern University. He received a BA in Mathematics and a PhD in Cell Physiology at the University of Chicago. Dr. Chandel is well recognized for his work on the role of mitochondria as signaling organelles.

Focus of work: Historically, reactive oxygen species (ROS) have been thought to be cellular damaging agents, lacking a physiological function. Accumulation of ROS and oxidative damage have been linked to multiple pathologies, including neurodegenerative diseases, diabetes, cancer, and premature aging. This guilt by association relationship left a picture of ROS as a necessary evil of oxidative metabolism, a product of an imperfect system. Yet few biological systems possess such flagrant imperfections, thanks to the persistent optimization of evolution, and it appears that oxidative metabolism is no different. More and more evidence suggests that low levels of ROS are critical for healthy cellular function. We are testing whether mitochondrial release of H2O2 has evolved as a method of communication between mitochondrial function and other cellular processes to maintain homeostasis (e.g. stem cell function and immune responses) and promote adaptation to stress (e.g. hypoxia). [northwestern.edu]

Nav’s Lab: Chandel Lab

Disclaimer: This blog is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice, and no doctor/patient relationship is formed. The use of information on this blog or materials linked from this blog is at the user's own risk. The content of this blog is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard, or delay in obtaining, medical advice for any medical condition they may have, and should seek the assistance of their health care professionals for any such conditions.

Comments

Read Our Comment Policy

Send this to friend

Facebook icon Twitter icon Instagram icon Pinterest icon Google+ icon YouTube icon LinkedIn icon Contact icon