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Updated: Aug 6, 2025

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Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the

Ananth Ponneri Babuharisankar1,2,3, Cheng-Liang Kuo2, Han-Yu Chou2

  • 1PhD program in molecular medicine, NHRI & NCU, Taoyuan, Taiwan.

Cell Death & Disease
|March 17, 2023
PubMed

Insights

Mitochondrial Lon acts as a chaperone to initiate mitophagy during hypoxia by stabilizing the FUNDC1-ULK1 complex at ER-mitochondria contact sites, promoting cell survival and cancer progression.

Area of Science:

  • Cellular Biology
  • Mitochondrial Dynamics
  • Autophagy Research

Background:

  • Hypoxia triggers mitophagy, a process where FUNDC1 acts as a receptor at ER-mitochondria contact sites (EMC).
  • The precise mechanism by which mitochondria sense stress and signal for mitophagy initiation remains elusive.
  • Mitochondrial Lon's role at EMC under stress was previously unknown.

Purpose of the Study:

  • To elucidate the mechanism by which mitochondrial Lon mediates mitophagy initiation under hypoxia.
  • To investigate Lon's role in stabilizing the FUNDC1-ULK1 complex at EMC.
  • To understand the implications of this pathway in cell survival and cancer progression.

Main Methods:

  • Investigated Lon localization and interaction with FUNDC1-ULK1 complex at EMC under hypoxia.
  • Utilized in vitro and in vivo models to study Lon-induced mitophagy.
  • Examined the role of mitochondrial Na+/Ca2+ exchanger (NCLX) in Lon-mediated mitophagy.

Main Results:

  • Lon accumulates at EMC under hypoxia and associates with the FUNDC1-ULK1 complex, inducing mitophagy via chaperone activity.
  • Lon-induced mitophagy is dependent on its binding with NCLX.
  • This interaction promotes FUNDC1-ULK1-mediated mitophagy at EMC.

Conclusions:

  • Lon acts as a novel mitochondrial chaperone initiating mitophagy under hypoxia.
  • Lon interacts with NCLX to facilitate FUNDC1-ULK1-mediated mitophagy at EMC.
  • This pathway is crucial for cell survival and contributes to cancer progression.

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