#31 – Navdeep Chandel, Ph.D.: metabolism, mitochondria, and metformin in health and disease

KEYPOINTS

• 01

  Mitochondria are signaling organelles, not just powerhouses

  Nav Chandel, a Northwestern professor of medicine and cell biology, says every talk he gives carries the same title: mitochondria as signaling organelles. Besides making ATP, they release molecules such as hydrogen peroxide and cytochrome c that tell the cell whether to live, die, proliferate or mount an immune response. In the mid-1990s most researchers assumed mitochondrial oxidants only leaked out when the organelle was damaged.

• 02

  Reactive oxygen species are mostly messengers, kept low by dozens of enzymes

  Chandel argues that superoxide and hydrogen peroxide, at physiological levels, carry information during exercise or when the immune system meets a virus or bacterium, and those responses are healthy, not pathological. Nature keeps at least 30 enzymes constantly mopping these species up so they stay at signaling levels. Only when they get out of control, or convert into more reactive forms, do they become lethal.

• 03

  High-dose antioxidants can blunt the benefits of exercise

  He cites exercise studies where muscle biopsies show the beneficial genes that vigorous exercise switches on. In those studies, high-dose antioxidants switched that response off. His caveat is that these were high doses, probably not what most people take. His reading is that the muscle may use hydrogen peroxide as the stress signal, so quenching it removes the message.

• 04

  Cytochrome c release is a key step in programmed cell death

  Chandel's early work centred on how mitochondria help decide a cell's fate. Proteins called BAX and BAK make pores in the mitochondria, letting the 13-kilodalton protein cytochrome c escape and set off a caspase cascade that kills the cell. He notes that 22 years later the basic finding still stands, which is rare in biology. A drug targeting a protein that controls this release is used to make cancer cells more sensitive to treatment.

• 05

  The mitochondrial genome is small but holds the respiratory chain's critical parts

  The nucleus holds about 20,000 genes, while mitochondrial DNA holds 37, including 13 that are essential for the respiratory chain to work. Complex I alone has 45 protein subunits, a few of them encoded in mitochondrial DNA.

• 06

  Mitochondrial decline with age may not be rate-limiting, and could even be adaptive

  Data show less mitochondrial DNA, more deletions and lower maximal oxidative capacity with age. But Chandel says we use maybe 10–20% of maximal capacity at rest and 40–50% in hard efforts. When his lab knocks a mitochondrial protein down from 100% to 50%, they see no pathology even under stress. He admits he is 'way out in outer space' here, but he sees no evidence that healthy tissue is limited by its mitochondria. Supplements to 'boost' them rest on dogma.

• 07

  Metformin works in three main places: the liver, the gut and immune cells

  Metformin is taken up selectively. It reaches the liver and kidney but not the heart very well, and it accumulates heavily in the gut, which is one reason some users get diarrhoea. The liver accounts for its glucose-lowering effect, and the colon for its effects on the microbiome. Chandel thinks the overlooked site is immune cells such as macrophages, where dampening inflammation may matter most.

• 08

  Metformin partially inhibits complex I and shifts the NAD+/NADH ratio

  By partly blocking complex I, metformin slows the conversion of NADH to NAD+, slightly lowers the charge of the mitochondrial 'battery' and slows the TCA cycle. Chandel stresses the ratio of NAD+ to NADH, not the absolute amount of NAD, as the key readout. That separates metformin from NAD supplements, which he believes raise total NAD without much change to the ratio.

• 09

  Tumors need working mitochondria, despite the Warburg story

  The classic view held that cancer cells rely on glycolysis, as seen in lactate production and glucose uptake on FDG-PET, so targeting glycolysis would spare normal tissue. Chandel argues that glycolysis is necessary but so is robust mitochondrial function. In most cancers, disabling the TCA cycle or respiratory chain prevents tumors from forming. A Science paper by Vander Heiden, Cantley and Thompson about a decade earlier reframed Warburg's observation as serving growth rather than energy.

• 10

  NAD precursors mostly end up in the liver

  Attia describes a Cell Metabolism paper from Josh Rabinowitz's group: orally given NR or NMN were taken up heavily by the liver, which made plenty of NAD there, but little reached other cells. Chandel thinks NR's plausible effects are metabolic actions in the liver, somewhat like metformin's, plus possible uptake by immune cells. He labels both as hypotheses and notes NAD is not his core expertise.