Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Neuromuscular disorders stemming from mitochondrial respiratory chain dysfunction are prevalent, severe, and lack effective treatments.
• Mitochondrial dysfunction is implicated in age-related neurodegeneration and proteostasis disruption.

Purpose of the Study:

• To investigate the role of protein degradation abnormalities in mitochondrial encephalomyopathies.
• To identify druggable targets for complex I deficiency-related neurodegeneration and proteostasis failure.

Main Methods:

• Forward genetic screen to identify mutations affecting neurodegeneration in the context of proteostasis dysfunction.
• Development of a Drosophila retina model for complex I deficiency.
• In vivo kinome screen to identify kinases involved in neurodegeneration and proteostasis failure.

Main Results:

• Complex I deficiency impacts both the ubiquitin/proteasome and autophagy/lysosome pathways.
• Reduction of RIOK kinases and Pelle kinase ameliorated neurodegeneration in the model.
• Targeting oxidative stress, but not RIOK1 or Pelle, normalized proteostasis markers.

Conclusions:

• Distinct pathways regulate neurodegeneration and protein degradation in complex I deficiency.
• This study introduces a valuable model for researching debilitating mitochondrial disorders.
• Kinases and oxidative stress pathways represent potential therapeutic avenues for mitochondrial encephalomyopathies.