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Drp1/Fis1-mediated mitochondrial fragmentation leads to lysosomal dysfunction in cardiac models of Huntington's

A U Joshi1, A E Ebert2, B Haileselassie3

  • 1Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, United States.

Journal of Molecular and Cellular Cardiology
|December 15, 2018
PubMed

Insights

Huntington's disease involves mitochondrial and lysosomal dysfunction in the heart, not just the brain. Targeting mitochondrial fission, like with P110, may improve cardiac function and cell survival in HD patients.

Area of Science:

  • Cardiovascular Biology
  • Neurodegenerative Diseases
  • Mitochondrial Biology

Background:

  • Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by CAG-repeat expansion in the Huntingtin (HTT) gene.
  • Mutant HTT (mHTT) affects multiple organ systems, including the cardiovascular system, with early signs of dysautonomia and circadian rhythm disruption.
  • While mitochondrial dysfunction is known in HD brain and muscle, its role in the heart remains understudied.

Purpose of the Study:

  • To investigate the role of mitochondrial dynamics and lysosomal function in the cardiac manifestations of Huntington's disease.
  • To explore therapeutic strategies targeting mitochondrial dysfunction in HD.

Main Methods:

  • Utilized H9C2 cells expressing a long polyglutamine repeat (Q73) and human iPSC-derived cardiomyocytes transfected with Q77.
  • Assessed mitochondrial structure, ATP production, and lysosomal function.
  • Examined the effect of inhibiting Drp1/Fis1-mediated mitochondrial fission using P110 in R6/2 mouse cardiac tissue.

Main Results:

  • Long polyglutamine expression induced excessive mitochondrial fission, reduced ATP production, and mitochondrial fragmentation in cardiac cells.
  • Observed coupled lysosomal dysfunction and accumulation of damaged mitochondria within lysosomes.
  • Inhibition of Drp1/Fis1-mediated mitochondrial damage improved mitochondrial function and cell survival.
  • Treatment with P110 ameliorated cardiac mitochondrial structure in R6/2 mice.

Conclusions:

  • Excessive mitochondrial fission and lysosomal dysfunction contribute to cardiac pathology in Huntington's disease.
  • Targeting mitochondrial dynamics, specifically the Drp1/Fis1 interaction, represents a potential therapeutic strategy for cardiac complications in HD.
  • Systemic therapeutic approaches are necessary as HD affects mitochondrial function across multiple organs, not solely the central nervous system.

Keywords:
BioenergeticsDrp1Fis1HeartHuntington's diseaseMitochondriaP110

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