Related Experiment Video

Updated: Sep 12, 2025

Dual-color Correlative Light and Electron Microscopy for the Visualization of Interactions between Mitochondria and Lysosomes
10:25

Dual-color Correlative Light and Electron Microscopy for the Visualization of Interactions between Mitochondria and Lysosomes

Published on: September 27, 2024

721

Impaired mitochondria-initiated crosstalk with lysosomes reciprocally aggravates mitochondrial defect through LManVI

Shengnan Li1, Zhaoliang Shan1, Guochun Zhao1

  • 1State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.

Nature Communications
|August 7, 2025
PubMed

Insights

Mitochondrial defects impair lysosomal function by downregulating alpha-mannosidase VI (LManVI). This creates a feedback loop worsening mitochondrial health, a pathway conserved in mammals.

Area of Science:

  • Cellular Biology
  • Mitochondrial Biology
  • Lysosome Biology

Background:

  • Mitochondria and lysosomes are crucial for cellular homeostasis.
  • Communication pathways between mitochondria and lysosomes during mitochondrial dysfunction are not well understood.

Purpose of the Study:

  • To investigate the communication between mitochondria and lysosomes under conditions of mitochondrial defects.
  • To elucidate the molecular mechanisms underlying this communication.
  • To explore the potential therapeutic implications for mitochondrial and lysosomal diseases.

Main Methods:

  • Utilized a Drosophila melanogaster (fruit fly) model with dMterf4 RNA interference (RNAi) to induce mitochondrial defects.
  • Analyzed the expression levels of lysosomal alpha-mannosidase VI (LManVI).
  • Investigated the molecular axis (Med8/Tfb4-E(z)/pho) involved in LManVI regulation.
  • Assessed the impact of LManVI downregulation on mitochondrial gene expression via PGC-1.

Main Results:

  • dMterf4 RNAi induced mitochondrial defects led to significant downregulation of lysosomal LManVI.
  • This downregulation occurred via the Med8/Tfb4-E(z)/pho axis, impairing lysosomal function.
  • Reduced LManVI further decreased mitochondrial gene expression by downregulating PGC-1, creating a positive feedback loop that exacerbated mitochondrial defects.
  • This mitochondria-lysosome crosstalk was observed to be conserved in mammalian cells.

Conclusions:

  • A novel communication mechanism between mitochondria and lysosomes in the context of mitochondrial defects has been identified.
  • This crosstalk involves a positive feedback loop where mitochondrial defects lead to lysosomal dysfunction, which in turn worsens mitochondrial status.
  • Targeting the mitochondria-lysosomes axis offers potential therapeutic strategies for mitochondrial and lysosomal diseases.

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