Quality control and biogenesis
Selective mitochondrial degradation
Mitophagy—the selective removal of damaged or surplus mitochondria via autophagy—is a key mechanism of mitochondrial quality control. Mutations in the PD-associated genes Pink1 and Parkin impair this process, suggesting that defective mitophagy contributes to the accumulation of dysfunctional mitochondria in certain inherited forms of Parkinson's disease. Our lab investigates how PD-related genes, mitochondrial dynamics factors, and cell stress pathways coordinate mitophagy and maintain mitochondrial integrity. Whole-genomes screens in mammalian cells have identified multiple pathways critical for degradation of mitochondria and the endoplasmic reticulum.
Mitochondrial proteostasis and Skd3 function
Even though mitochondria famously contain own genome, in reality 99% of its proteome is encoded by the nuclear genome. Nuclearly encoded mitochondrial proteins are translated by cytosolic ribosomes and imported into the organelle through the translocases of the outer membrane and inner membrane (TOM and TIM complexes). This necessity for import has consequences for protein quality control: mitochondrial precursor polypeptides must be unfolded during their threading through the narrow passage of the import machinery, and therefore the proteins must refold accurately and rapidly upon entry to avoid misfolding and aggregation. Robust mitochondrial protein folding and surveillance systems are therefore essential for mitochondrial function and human health.
Our research focuses on Skd3, a AAA⁺ ATPase located in the intermembrane space. Skd3 uses ATP hydrolysis to disaggregate misfolded proteins and restore them to their native state. Mechanistically, Skd3 assembles into hexamers that recognize and extract proteins from aggregates; recruitment of a second hexamer produces a dodecameric folding cagethat facilitates client refolding. Highlighting its importance, mutations in Skd3 cause two severe mitochondrial disorders—3-methylglutaconic aciduria type 7 (MGCA7) and severe congenital neutropenia (SCN).
In collaboration with the Shan laboratory (CCE), we are investigating how Skd3 safeguards mitochondrial protein quality control, with the goals of defining its chaperone mechanisms and understanding how its dysfunction impacts neuronal and hematopoietic health.