Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration

Abstract

MCL-1, an anti-apoptotic BCL-2 family member that is essential for the survival of multiple cell lineages, is also among the most highly amplified genes in cancer. Although MCL-1 is known to oppose cell death, precisely how it functions to promote survival of normal and malignant cells is poorly understood. Here, we report that different forms of MCL-1 reside in distinct mitochondrial locations and exhibit separable functions. On the outer mitochondrial membrane, a MCL-1 isoform acts like other anti-apoptotic BCL-2 molecules to antagonize apoptosis, whereas an amino-terminally truncated isoform of MCL-1 that is imported into the mitochondrial matrix is necessary to facilitate normal mitochondrial fusion, ATP production, membrane potential, respiration, cristae ultrastructure, and maintenance of oligomeric ATP synthase. Our results provide insight into how MCL-1's surprisingly diverse salutary functions may control the survival of both normal and cancer cells.

MCL1 Enhances the Survival of CD8 + Memory T Cells after Viral Infection

“…It is also possible that MCL1 affects cellular processes distinct from those involved in cell survival. Some studies suggest that forms of MCL1 may play a role in normal mitochondrial physiology (35) and autophagy (36), both of which affect T cell differentiation (32,37). Further studies are necessary to elucidate ϩ T cell numbers were determined.…”

Bok Is Not Pro-Apoptotic But Suppresses Poly ADP-Ribose Polymerase-Dependent Cell Death Pathways and Protects against Excitotoxic and Seizure-Induced Neuronal Injury

“…Hippocampal damage has been examined previously in mice lacking multi-BH domain Bcl-2 family members, including Bak (Fannjiang et al, 2003), Bad (Giménez-Cassina et al, 2012), Mcl-1 (Mori et al, 2004), and Bcl-w (Murphy et al, 2007). Bak in particular has been shown to also exert protective activities during seizure-induced injury, but the interpretation of those previous reports are complicated by altered electrographic seizures in the gene-deficient mice (Fannjiang et al, 2003;Murphy et al, 2007;Giménez-Cassina et al, 2012) and the need to use heterozygous mice (Mori et al, 2004). Our quantitative EEG analysis in bok-deficient mice excludes the observed phenotype being attributable to altered seizure susceptibility.…”

“…Status epilepticus was triggered by a unilateral microinjection of KA into the amygdala. In this model, the resulting seizure-induced cell death is mainly restricted to the ipsilateral hippocampal CA3 subfield (Murphy et al, 2010), in which Bok is known to be enriched (Lein et al, 2004, Newrzella et al, 2007. WT and bok-deficient mice were subjected to status epilepticus for 40 min, and, 72 h later, seizure-induced neuronal death was examined (Fig.…”

“…Interestingly, this role of Bok mostly requires the presence of Bax and Bak, suggesting that Bok activities may be distinct from those of Bax-like proteins (Ke et al, 2012;Echeverry et al, 2013). Bok is expressed in the cerebral cortex and highly enriched in the CA3 subfield of the hippocampus (Lein et al, 2004;Newrzella et al, 2007;, which are areas of the brain vulnerable to ischemic and seizure-induced injury. The significance of this is unknown because the potential physiological or pathophysiological role of Bok in the CNS has yet to be explored.…”

Myeloid cell leukemia 1 (MCL-1), an unexpected modulator of protein kinase signaling during invasion

“…Proteolytically cleaved amino-truncated MCL-1 can localise to the inner mitochondrial membrane and is important for mitochondrial structure and physiology. 48,49 Furthermore, cell cycle progression by MCL-1 is also mediated through the direct recruitment and inhibition of CDK1, due a reduced capacity of CDK1 to bind to Cyclin 1B. 50 In this manner MCL-1 binding may subvert the interaction of other target proteins thereby restricting kinase activity eg by binding to CDK1 and preventing cell cycle progression.…”