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Malic enzyme 2 suppresses PINK1-Parkin-mediated mitophagy by stabilizing ATAD3A via competitive interaction with

Qian Liu1, Lei Su1, Xiaoyun Wei1

  • 1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China.

Cell Death & Disease
|March 25, 2026
PubMed

Insights

Malic enzyme 2 (ME2) depletion enhances mitophagy by disrupting TRIM25-ATAD3A binding, leading to PINK1 accumulation. This process suppresses hepatoma cell proliferation, revealing ME2

Area of Science:

  • Mitochondrial biology
  • Cellular metabolism
  • Cancer research

Background:

  • Malic enzyme 2 (ME2) is involved in the TCA cycle and NADP+/NADPH balance, implicated in cancer.
  • ME2 regulates mitochondrial biogenesis and fusion, but its role in mitophagy is unknown.

Purpose of the Study:

  • To investigate the role of Malic enzyme 2 (ME2) in mitophagy regulation.
  • To elucidate the molecular mechanism by which ME2 influences mitophagy.
  • To assess the impact of ME2-mediated mitophagy on hepatoma cell proliferation.

Main Methods:

  • Depletion of Malic enzyme 2 (ME2) using knockdown techniques.
  • Analysis of the interaction between ME2, TRIM25, and ATAD3A.
  • Assessment of PINK1 ubiquitination and degradation.
  • Measurement of mitophagy flux and mitochondrial homeostasis.
  • Evaluation of hepatoma cell proliferation and rescue experiments with mitophagy inhibitors.

Main Results:

  • ME2 depletion enhances PINK1-Parkin-mediated mitophagy.
  • ME2 competes with TRIM25, disrupting TRIM25-ATAD3A binding.
  • Loss of ME2 strengthens TRIM25-ATAD3A interaction, leading to ATAD3A degradation.
  • Increased PINK1 accumulation and mitophagy activation.
  • ME2 knockdown suppresses hepatoma cell proliferation via hyperactivated mitophagy.

Conclusions:

  • Malic enzyme 2 (ME2) plays an unrecognized role in mitochondrial quality control.
  • The ME2-ATAD3A-PINK1 axis is a novel regulatory node for mitophagy.
  • Targeting ME2 or mitophagy could be a potential strategy for hepatoma treatment.

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