1. Academic Validation
  2. A mitochondrial membrane-bridging machinery mediates signal transduction of intramitochondrial oxidation

A mitochondrial membrane-bridging machinery mediates signal transduction of intramitochondrial oxidation

  • Nat Metab. 2021 Sep;3(9):1242-1258. doi: 10.1038/s42255-021-00443-2.
Li Li 1 Devon M Conradson 1 Vinita Bharat 1 Min Joo Kim 1 Chung-Han Hsieh 1 Paras S Minhas 2 3 Amanda M Papakyrikos 1 4 Aarooran Sivakumaran Durairaj 2 Anthony Ludlam 5 Katrin I Andreasson 2 6 7 Linda Partridge 8 9 Michael A Cianfrocco 5 Xinnan Wang 10 11 12
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
  • 2 Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • 3 Neurosciences Intradepartmental Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
  • 4 Graduate Program in Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
  • 5 Life Sciences Institute & Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA.
  • 6 Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • 7 Program in Immunology, Stanford University, Stanford, CA, USA.
  • 8 Institute of Healthy Ageing, Genetics, Evolution and Environment, University College London, London, UK.
  • 9 Max Planck Institute for Biology of Ageing, Cologne, Germany.
  • 10 Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 11 Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 12 Maternal & Child Health Research Institute, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
Abstract

Mitochondria are the main site for generating Reactive Oxygen Species, which are key players in diverse biological processes. However, the molecular pathways of redox signal transduction from the matrix to the cytosol are poorly defined. Here we report an inside-out redox signal of mitochondria. Cysteine oxidation of MIC60, an inner mitochondrial membrane protein, triggers the formation of disulfide bonds and the physical association of MIC60 with Miro, an outer mitochondrial membrane protein. The oxidative structural change of this membrane-crossing complex ultimately elicits cellular responses that delay Mitophagy, impair cellular respiration and cause oxidative stress. Blocking the MIC60-Miro interaction or reducing either protein, genetically or pharmacologically, extends lifespan and health-span of healthy fruit flies, and benefits multiple models of Parkinson's disease and Friedreich's ataxia. Our discovery provides a molecular basis for common treatment strategies against oxidative stress.

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