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Updated: Nov 9, 2025

Time-Lapse Video Microscopy for Assessment of EYFP-Parkin Aggregation as a Marker for Cellular Mitophagy
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Time-Lapse Video Microscopy for Assessment of EYFP-Parkin Aggregation as a Marker for Cellular Mitophagy

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Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination

Yumiko Oshima1,2, Etienne Cartier1,2, Liron Boyman1,3

  • 1Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD.

The Journal of Cell Biology
|April 14, 2021
PubMed

Insights

Reduced mitochondrial translation fidelity triggers ubiquitination of inner mitochondrial membrane proteins, initiating autophagy for damaged mitochondria removal in Parkin-deficient cells. This pathway involves outer mitochondrial membrane severing and selective targeting of specific mitochondria.

Area of Science:

  • Cell Biology
  • Mitochondrial Biology
  • Autophagy Research

Background:

  • Mitochondrial dysfunction is implicated in various diseases.
  • Mitochondrial protein quality control is crucial for cellular health.
  • Mechanisms of selective mitochondrial degradation are actively investigated.

Purpose of the Study:

  • To investigate the cellular response to reduced mitochondrial translation fidelity (MTF).
  • To elucidate the role of protein ubiquitination and autophagy in managing mitochondrial damage.
  • To compare the response in Parkin-deficient versus Parkin-overexpressing cells.

Main Methods:

  • Analysis of ubiquitination of inner mitochondrial membrane (IMM) proteins.
  • Investigation of outer mitochondrial membrane (OMM) severing.
  • Assessment of autophagy recruitment and inhibition.
  • Study of mitochondrial distribution and Parkin targeting.

Main Results:

  • Reduced MTF causes selective IMM protein ubiquitination in mitochondria with severed OMM.
  • Ubiquitinated IMM recruits autophagy machinery, and its inhibition causes accumulation of damaged mitochondria.
  • This process requires active mitochondrial translation and fission, independent of Bax/Bak.
  • Parkin-deficient cells utilize OMM severing and autophagy for damaged mitochondria, while Parkin-overexpressing cells show Drp1-independent OMM ubiquitination.

Conclusions:

  • Parkin-deficient cells employ a Drp1-mediated pathway involving OMM severing and autophagy to clear mitochondria with reduced MTF.
  • Mitochondria with high cytochrome c/CPOX are mitophagy intermediates.
  • This study reveals a novel adaptive mechanism for mitochondrial proteotoxicity.

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