#66 – Vamsi Mootha, MD: Aging, T2D, cancer, dementia, Parkinson’s—do all roads lead to mitochondria?

KEYPOINTS

• 01

  Mitochondria are domesticated bacteria with a stripped-down genome

  Over evolution, about a thousand genes from the original bacterium were lost or moved to the nucleus. The human mitochondrial genome is now about 16,000 base pairs and encodes 13 proteins, two ribosomal RNAs and 22 tRNAs. Mootha notes the malaria parasite's mitochondria encode only three proteins, while Giardia ('beaver fever') has lost its mitochondrial DNA altogether.

• 02

  Mitochondrial disease isn't just 'maternal'

  There are about 250 distinct syndromes caused by mutations in mitochondrial DNA. But most of the roughly 1,000 proteins that mitochondria need are encoded in the nucleus, so many disorders are recessive nuclear mutations rather than maternally inherited. Mootha says clinical training overemphasised maternal inheritance because those cases were easiest to recognise.

• 03

  Why mitochondrial DNA comes from your mother

  An unfertilized egg holds about half a million copies of mitochondrial DNA, more than any other cell, while a sperm has a few hundred at best. Beyond being outnumbered, sperm mitochondria are tagged with ubiquitin and actively destroyed after fertilization.

• 04

  Mitochondria turn over within days

  In non-dividing tissues such as muscle and neurons, Mootha estimates the half-life of mitochondrial components at a few days, so the body is constantly building and recycling them. Counting individual mitochondria is ambiguous because they continually fuse and divide, so copies of mitochondrial DNA are the better unit.

• 05

  NAD is both an electron carrier and a consumable

  NAD shuttles electrons in the electron transport chain to power ATP production, but sirtuins and DNA-damage enzymes also use it up. That's why NAD can fall quickly in cells with damaged DNA. Muscle biopsies show NAD, mitochondrial content and VO2 max all declining with age, but Mootha says the open question is whether sick mitochondria cause tissue aging or simply accompany it.

• 06

  Too much oxygen, not just too little ATP, may drive some mitochondrial disease

  The textbook view is an energy shortage, but Mootha's lab finds that glycolysis largely defends ATP at rest. Because mitochondria consume most of the oxygen we breathe, broken ones leave unused oxygen in tissues, which can be toxic. Patients often show unusually high oxygen in venous blood.

• 07

  Reduced mitochondrial function shows up before type 2 diabetes

  Papers in 2003–04 from Mootha, Leif Groop, David Altshuler, Ron Kahn, Gerald Shulman and others found that healthy people with a family history of diabetes had slightly lower expression across the whole set of mitochondrial genes, fewer mitochondria and lower VO2 max. Fifteen years later, whether this causes diabetes or reflects some upstream factor remains unresolved. Mootha's team was attempting to answer it with Mendelian randomization.

• 08

  Partly blocking the electron transport chain can extend life in worms

  RNAi screens by Gary Ruvkun and Cynthia Kenyon found electron-transport genes among those whose disruption lengthened worm lifespan, and also among those that shortened it. One explanation is dose: gentle inhibition triggers protective responses, while severe loss kills. Mootha suggests metformin, a complex I inhibitor, may work through such a mild hit.

• 09

  Exercise is the best known way to renew mitochondria

  Mootha says no drug yet rejuvenates mitochondria directly. Exercise both clears damaged ones and builds new ones. Both he and Attia are skeptical of 'exercise in a pill' headlines; Attia points to crude news coverage of irisin.