Ubiquitin-proteasome dependent mitochondrial protein quality control

Dysfunctional mitochondria cause many neurodegenerative disorders and with aging in general, mechanisms of mitochondrial quality control are essential for cellular function. Keeping mitochondria in a healthy state is a complex process, which is tightly regulated by several mitochondrial quality control systems. An ubiquitin-mediated proteasome-dependent protein degradation pathway, termed outer mitochondrial-associated degradation (OMMAD), was recently described. OMMAD provides mitochondrial protein quality control to prevent mitochondrial damage. Up until now, four outer mitochondrial membrane-anchored RING finger ubiquitin ligases as well as the AAA-ATPase p97 were described as OMMAD components. Here, we further characterize the mitochondrial RING finger protein MARCH9. We found that MARCH9 is an unstable protein degraded in a proteasomal-dependent manner. Furthermore MARCH9 interacts physically with both mitofusins, Mfn1 and Mfn2, both involved in the mitochondrial fusion. The dominant-negative mutant of MARCH9 was found to block mitochondrial fusion and cause mitochondrial fragmentation. Taken together, our result suggests a role for MARCH9 in mitochondrial quality control and further integrates OMMAD into mitochondrial physiology.
Not only reactive oxygen species are involved in the aging process and in neurodegeneration, other stressors such as reactive nitrogen species, especially nitric oxide (NO) also cause such damage. Constant low level damage caused by NO to mitochondria eventually results in the loss of mitochondrial integrity and ultimately mitochondrial dysfunction. NO can directly modify mitochondrial proteins in a reaction, called S-nitrosylation. In response to low level of exogenous NO but also in the absence of such exogenous nitrosative stress, S-nitrosylated proteins are present in mitochondria. Furthermore, we found that upon inhibition of the proteasome, levels of S-nitrosylated proteins are increased and that the AAA-ATPase p97 is involved in the translocation of such S-nitrosylated proteins from mitochondria into the cytosol.
Taken together, OMMAD components are necessary for maintaining mitochondrial integrity on the molecular and on the organellar level through the removal of damaged proteins and through regulating mitochondrial morphology.