A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders

Area of Science:

• Cellular Biology
• Mitochondrial Biology
• Neurogenetics

Background:

• Mitochondrial DNA (mtDNA) deletions lead to clonal expansion in skeletal muscle, causing oxidative phosphorylation (OXPHOS) dysfunction.
• These deletions initially affect perinuclear mitochondria, leading to localized dysfunction before spreading throughout muscle fibers.
• Mito-nuclear signaling is hypothesized to be crucial in the accumulation and spread of mtDNA deletions.

Purpose of the Study:

• To investigate the role of mito-nuclear signaling in the spread of mitochondrial dysfunction within muscle fibers.
• To characterize cellular responses to varying degrees of OXPHOS dysfunction and ragged red fibers in patients with mtDNA maintenance disorders.

Main Methods:

• Utilized imaging mass cytometry to analyze protein levels in skeletal muscle fibers from patients with mtDNA maintenance disorders.
• Quantified levels of OXPHOS proteins and a mitochondrial mass marker.
• Assessed protein markers of key signaling pathways, proteostasis, and mitochondrial metabolism.

Main Results:

• Combined Complex I and IV deficiency was the most prevalent OXPHOS defect.
• In deficient fibers, remaining OXPHOS complexes were often upregulated beyond the typical increase in mitochondrial mass seen in ragged red fibers.
• Oxidative phosphorylation-deficient fibers showed increased abundance of proteins involved in proteostasis (e.g., HSP60, LONP1) and mitochondrial metabolism regulation (e.g., PHB1).

Conclusions:

• Cellular responses to mitochondrial dysfunction are heterogeneous and depend on the specific combination of deficient OXPHOS complexes.
• Upregulation of remaining OXPHOS complexes and activation of proteostasis/metabolic pathways represent adaptive responses to mitochondrial stress.
• Understanding these complex cellular responses is key to deciphering disease mechanisms in mtDNA maintenance disorders.