MCL-1 Regulates Mitochondrial Dynamics and Turnover
- Author(s): Moyzis, Alexandra Grady
- Advisor(s): Gustafsson, Asa B.
- et al.
Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic protein that is highly expressed in the myocardium and plays a critical role in maintaining cardiac homeostasis. Cardiac-specific MCL-1-knockout mice develop rapid cardiac dysfunction and cardiomyopathy but show little activation of apoptotic cell death. Instead, loss of MCL-1 resulted in atypical mitochondrial morphology and function. This suggests that besides its anti-apoptotic role, MCL-1 may have broader functions in regulating mitochondrial dynamics and function. MCL-1 localizes to two different mitochondrial locations, both on the outer mitochondrial membrane (MCL-1OM) and a shorter cleaved form resides in the mitochondrial matrix (MCL-1Matrix). Cardiac-specific ablation of MCL-1 resulted in the loss of MCL-1 at both of these distinct mitochondrial locations, so it is unknown what their respective functional contributions are. My studies have focused on MCL-1 on the outer mitochondrial membrane (MCL-1OM).
I have found that MCL-1OM regulates DRP-1-mediated fission as an adaptive response to stress. I have also developed a novel MCL-1OM transgenic mouse model and observed that MCL-1OM overexpression results in enhanced mitochondrial fission in vivo as well. Additionally, MCL-1 overexpression facilitates mitochondrial clearance in response to stress. My data suggests that MCL-1 does not act as a mitophagy receptor itself, but likely induces turnover through the mitophagy receptor BNIP3. Finally, MCL-1 inhibits general autophagy in response to energetic stress, but does not exert this effect under circumstances that induce oxidative stress and cellular damage. Taken together, these findings suggest that in addition to its anti-apoptotic role, MCL-1OM has additional functions in regulating DRP1-mediated mitochondrial fission and facilitating mitochondrial clearance via the mitophagy receptor BNIP3. My dissertation also extends concerns about potential cardiotoxicity for chemotherapeutics targeting MCL-1.