Mitochondria dynamics and functions regulation by the ubiquitin-proteasome system

The ubiquitin-proteasome system (UPS) plays an important role in maintaining cellular homeostasis. Within the UPS, E3 ubiquitin ligases are believed to determine substrate specificity. Recent studies demonstrated a link between various E3 ligases, such as Parkin, Mul1, and others to mitochondria dynamics and function under normal and stress conditions; however, whether additional E3 ligases regulate various mitochondria functions is currently unknown.

Here we utilized genetics, advanced microscopy, and biochemistry methods to investigate E3 ligases in the context of mitochondria biogenesis and functions. We monitored the localization of various E3 ligase components in cells grown under optimal conditions as well as in response to small molecules that disrupt mitochondria function. In addition, we generated CRISPR/Cas9 knock-out (KO) cells for E3 ligase complex subunits and examined whether mitochondria function and mitophagy is altered in these cells. Future proteomics approaches will be used to elucidate the substrates that mediate targeting of the E3 ligase components to the mitochondria as well as those involved in E3 ligase-mediated regulation of mitochondria functions. As alterations in mitochondrial function are associated with various human diseases, our research may shed light on the molecular mechanism involved with therapeutic implications.