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Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program

Mikhail Y Vyssokikh1, Susanne Holtze2, Olga A Averina1,3

  • 1Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia.

Proceedings of the National Academy of Sciences of the United States of America
|March 11, 2020
PubMed

Insights

Mitochondria prevent reactive oxygen species (ROS) using bound kinases, maintaining mild depolarization that slows aging. This protective mechanism declines with age in mice but persists in long-lived naked mole rats and bats.

Area of Science:

  • Mitochondrial biology
  • Aging research
  • Biochemistry

Background:

  • Mitochondria generate reactive oxygen species (ROS), contributing to aging.
  • Hexokinases and creatine kinase bound to mitochondrial membranes are key players in regulating mitochondrial function.
  • Mitochondrial ATP/ADP antiporter facilitates substrate and product transport for kinase activity.

Purpose of the Study:

  • To investigate the role of mitochondrial kinases and mild depolarization in preventing ROS generation.
  • To compare the age-dependent changes in these protective systems across different species.
  • To understand the contribution of mitochondrial anti-aging mechanisms to longevity.

Main Methods:

  • Comparative analysis of mitochondrial systems in mice, naked mole rats, and bats.
  • Investigation of hexokinase and creatine kinase binding to mitochondrial membranes.
  • Measurement of mitochondrial membrane potential (∆ψ) and ROS generation.

Main Results:

  • Bound hexokinases and creatine kinase maintain mitochondrial ATP/ADP cycling, leading to mild depolarization (lower ∆ψ).
  • This mild depolarization effectively inhibits mitochondrial ROS (mROS) generation.
  • Age-dependent loss of mild depolarization in mice correlates with increased ROS-mediated damage, while naked mole rats and bats retain this mechanism, exhibiting slower aging.

Conclusions:

  • Mitochondrial mild depolarization, maintained by bound kinases, is a critical anti-aging mechanism.
  • The persistence of this system in long-lived species like naked mole rats and bats contributes to their extended lifespan.
  • Targeting these mitochondrial pathways could offer strategies for combating age-related decline.
Keywords:
agingantioxidantmild depolarizationmitochondrianaked mole rat

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