Direct Regulation of Mitochondrial Fatty Acid Oxidation by Anti-Apoptotic MCL-1

Abstract

Apoptosis is a form of programmed cell death essential to normal development and tissue homeostasis. BCL-2 family proteins are key regulators of the apoptotic pathway and control the life-death decision rendered by cells in response to stress. Localized mainly at the outer mitochondrial membrane, BCL-2 family proteins engage in a variety of heterodimeric and homooligomeric protein interactions, mediated by their conserved BCL-2 Homology (BH) domains, to determine cell fate. MCL-1 is a member of the BCL-2 family and regulates cell death by exerting potent anti-apoptotic activity. At the mitochondria, MCL-1 neutralizes pro-apoptotic BCL-2 family members, including NOXA, PUMA, BIM, and BAK, such that its pathologic overexpression contributes to the development and chemoresistance of many human cancers. Emerging data underscore that MCL-1 has unique attributes among BCL-2 anti-apoptotic proteins with respect to both amino acid composition and function. For example, unlike its anti-apoptotic homologues, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in organism homeostasis. Thus, to explore novel mechanistic role(s) of MCL-1, we undertook an exploratory proteomic study to uncover potential targets of the MCL-1 BH3 domain. Here, we report that MCL-1, and specifically its mitochondrial matrix isoform, directly engages very long chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid β-oxidation pathway. The interaction is mediated by the α-helical MCL-1 BH3 domain, which binds VLCAD at a surface groove adjacent to the enzyme active site. Deletion of endogenous Mcl-1 impairs fatty acid β-oxidation, resulting in selective accumulation of long-chain fatty acylcarnitines, as seen in VLCAD-deficient patients. Our identification of a BH3-mediated interaction between MCL-1 and VLCAD reveals a separable, gain-of-function role for MCL-1 in the regulation of lipid metabolism.