Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice

Nat Commun. 2014 May 12:5:3837. doi: 10.1038/ncomms4837.

Abstract

Mitochondrial function is an important determinant of the ageing process; however, the mitochondrial properties that enable longevity are not well understood. Here we show that optimal assembly of mitochondrial complex I predicts longevity in mice. Using an unbiased high-coverage high-confidence approach, we demonstrate that electron transport chain proteins, especially the matrix arm subunits of complex I, are decreased in young long-living mice, which is associated with improved complex I assembly, higher complex I-linked state 3 oxygen consumption rates and decreased superoxide production, whereas the opposite is seen in old mice. Disruption of complex I assembly reduces oxidative metabolism with concomitant increase in mitochondrial superoxide production. This is rescued by knockdown of the mitochondrial chaperone, prohibitin. Disrupted complex I assembly causes premature senescence in primary cells. We propose that lower abundance of free catalytic complex I components supports complex I assembly, efficacy of substrate utilization and minimal ROS production, enabling enhanced longevity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Aging, Premature
  • Animals
  • Cell Line
  • Electron Transport Complex I / metabolism*
  • HeLa Cells
  • Humans
  • Liver / metabolism*
  • Longevity / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / metabolism*
  • NADH Dehydrogenase / metabolism
  • Oxidation-Reduction
  • Oxidative Stress
  • Prohibitins
  • Proteomics
  • RNA Interference
  • RNA, Small Interfering
  • Reactive Oxygen Species / metabolism*
  • Repressor Proteins / genetics

Substances

  • Prohibitins
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Repressor Proteins
  • NADH Dehydrogenase
  • Electron Transport Complex I
  • NDUFB9 protein, human
  • NDUFS3 protein, human