# Malic enzyme 2 suppresses PINK1-Parkin-mediated mitophagy by stabilizing ATAD3A via competitive interaction with TRIM25

## TL;DR

Malic enzyme 2 suppresses mitophagy by stabilizing ATAD3A, and its depletion enhances mitophagy, affecting mitochondrial health and cell proliferation.

## Contribution

This study reveals a novel regulatory mechanism of mitophagy involving malic enzyme 2, TRIM25, and ATAD3A.

## Key findings

- ME2 depletion enhances PINK1-Parkin-mediated mitophagy by disrupting TRIM25-ATAD3A binding.
- Loss of ME2 leads to ATAD3A ubiquitination and degradation, increasing PINK1 levels and mitophagy activation.
- Pharmacological inhibition of mitophagy rescues cell proliferation in ME2-knockdown hepatoma cells.

## Abstract

Malic enzyme 2 (ME2), a pivotal enzyme related to the tricarboxylic acid (TCA) cycle, has been implicated in multiple cancers due to its overexpression and metabolic role in regulating the NADP+/NADPH balance. Malic enzyme 2 has been reported to regulate mitochondrial biogenesis and fusion; however, whether malic enzyme 2 participates in mitophagy regulation has remained unclear. Here, we reported that malic enzyme 2 depletion enhances PINK1-Parkin-mediated mitophagy. Mechanistically, ME2 competes with the E3 ubiquitin ligase TRIM25, disrupting its binding with ATPase family AAA domain-containing protein 3 A (ATAD3A), a mitochondrial protein crucial for the degradation of PINK1. Loss of malic enzyme 2 strengthens the TRIM25-ATAD3A interaction, resulting in ATAD3A ubiquitination and proteasomal degradation. The consequent PINK1 accumulation drives mitophagy activation. Hyperactivated mitophagy caused by malic enzyme 2 knockdown disrupts mitochondrial homeostasis, which suppresses the proliferative capacity of hepatoma cells. Moreover, pharmacological inhibition of mitophagy partially rescued the suppressed cell proliferation in the malic enzyme 2-knockdown cells. Our findings reveal a previously unrecognized role of malic enzyme 2 in mitochondrial quality control and highlight the ME2-ATAD3A-PINK1 axis as a potential regulatory node for mitophagy modulation.