Mcl-1-mediated mitochondrial fission protects against stress but impairs cardiac adaptation to exercise

• Published in: Journal of molecular and cellular cardiology Vol. 146; pp. 109 - 120
• Main Authors: Moyzis, Alexandra G., Lally, Navraj S., Liang, Wenjing, Leon, Leonardo J., Najor, Rita H., Orogo, Amabel M., Gustafsson, Åsa B.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2020
• Subjects: Drp1; Fission; Heart; Mcl-1; Mitochondria; Heart; Mcl-1; Mitochondria; Fission; Drp1
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2020.07.009

Myeloid cell leukemia-1 (Mcl-1) is a structurally and functionally unique anti-apoptotic Bcl-2 protein. While elevated levels of Mcl-1 contribute to tumor cell survival and drug resistance, loss of Mcl-1 in cardiac myocytes leads to rapid mitochondrial dysfunction and heart failure development. Although Mcl-1 is an anti-apoptotic protein, previous studies indicate that its functions extend beyond regulating apoptosis. Mcl-1 is localized to both the mitochondrial outer membrane and matrix. Here, we have identified that Mcl-1 in the outer mitochondrial membrane mediates mitochondrial fission, which is independent of its anti-apoptotic function. We demonstrate that Mcl-1 interacts with Drp1 to promote mitochondrial fission in response to various challenges known to perturb mitochondria morphology. Induction of fission by Mcl-1 reduces nutrient deprivation-induced cell death and the protection is independent of its BH3 domain. Finally, cardiac-specific overexpression of Mcl-1OM, but not Mcl-1Matrix, contributes to a shift in the balance towards fission and leads to reduced exercise capacity, suggesting that a pre-existing fragmented mitochondrial network leads to decreased ability to adapt to an acute increase in workload and energy demand. Overall, these findings highlight the importance of Mcl-1 in maintaining mitochondrial health in cells. [Display omitted] •Mcl-1 interacts with Drp1 to promote mitochondrial fission during stress.•Drp1-mediated fission is independent of Mcl-1's traditional anti-apoptotic function.•Overexpression of Mcl-1OM in heart leads to a shift in the balance towards fission.•Pre-existing fragmented mitochondria are associated with reduced exercise capacity.•Our findings highlight the importance of Mcl-1 in maintaining mitochondrial health.