Delving deeper: MCL-1's contributions to normal and cancer biology

Abstract

BCL-2 molecules are regulators of programmed cell death and defects in this pathway contribute to human diseases. One family member, MCL-1, is unique because its expression is tightly regulated and it is essential for promoting the survival of myriad cellular lineages. Additionally, MCL-1 promotes the maintenance of normal mitochondrial morphology and energy production. Dissection of these functions revealed recently that they depend on separate mitochondrial sublocalizations. MCL-1's antiapoptotic activity is restricted to the outer mitochondrial membrane (OMM), whereas its function in mitochondrial physiology requires localization to the matrix. These findings provide an attractive model for how MCL-1's diverse functions may contribute to normal cell homeostasis and function. MCL-1 is highly amplified in human cancer, suggesting that these functions may contribute to malignant cell growth and evasion of apoptosis.

Figure 1. Role of Anti-Apoptotic Regulators during Hematopoiesis

All blood cell lineages arise from a hematopoietic stem cell (HSC) that is capable of self-renewal and has an indefinite life-span. HSCs give rise to multi-potent progenitors (MPPs) which still retain the ability to give rise to all blood cell lineages, but lack long-term self-renewal capacity. MPPs can produce two progenitors, common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs). CLPs can produce the lymphoid lineages (B, T, and perhaps NK cells). CMPs produce at least two other oligopotent progenitor populations, the megakaryocyte erythroid progenitor (MEP) that produce red blood cells (erythrocytes) and megakaryocytes (generates platelets) and the granulocyte monocyte progenitor (GMP) that produces granulocytes (neutrophils) and monocytes (macrophages). Listed beside each differentiation step or progenitor population are the known anti-apoptotic regulators that promote the survival of the given population. Anti-apoptotic MCL-1 has multiple checkpoints as it has been illustrated to be critical for the survival of several multipotent and oligopotent progenitor populations (HSC, CMP, CLP, and GMP) and has been shown to be critical for the differentiation of granulocytes, but interestingly not the monocyte lineage. A1-a, a murine ortholog of BFL-1, and other A1 isoforms have also been shown to play an important role in promoting neutrophil survival in response to stress, but are not absolutely required for development, but primarily effect mature cell survival (indicated by open arrowhead). A1 isoforms also play a role, but are not essential in lymphoid development. In the erythroid lineage, it appears that anti-apoptotic BCL-X_L is the essential survival molecule, but unpublished data indicates that MCL-1 may also play an essential role during early differentiation. In the megakaryocytic lineage it appears that while neither MCL-1 nor BCL-X_L is solely responsible for survival, the two pro-survival molecules appear to have overlapping functions (indicated by open arrowheads) in promoting megakaryocyte survival. The critical anti-apoptotic regulators of some lineages including NK cells are still uncertain.

Figure 2. Model for MCL-1's Potential Functions at the Mitochondria

MCL-1 possesses multiple functions at the mitochondria. (a) On the outer mitochondrial membrane (OMM), MCL-1 functions like other anti-apoptotic BCL-2 family members where it acts to prevent the activation of BAX and BAK to prevent cell death. MCL-1 can directly bind BH3-only family members, such as BIM, sequestering them away from the pro-apoptotic effectors BAX or BAK. Alternatively, MCL-1 may directly bind BAX and BAK and maintain them in an inactive conformation. (b) During mitochondrial importation, the full-length MCL-1 is proteolytically truncated on its amino-terminus. The truncated, matrix localized MCL-1 resides within the inner mitochondrial membrane where it functions to maintain mitochondrial cristae ultrastructure and promotes the assembly of the electron transport chain complexes into higher-order assemblies known as supercomplexes (SC). The assembly into supercomplexes has been shown to facilitate electron transport efficiency and reduce the production of deleterious reactive oxygen species. Additionally, matrix-localized MCL-1 facilitates the assembly of the higher-order assembly of the ATP synthase complexes into dimers and oligomers. Proper assembly of oligomeric ATP synthase has been implicated in being an important determinate of inner membrane cristae structure. Genetic ablation of Mcl-1 results in defects in both supercomplex and ATP synthase oligomer assembly. Whether MCL-1 acts directly or indirectly to facilitate these macromolecular assemblies of the electron transport supercomplexes or ATP synthase oligomers is still unclear.

Figure 3. Model for Possible MCL-1 Functions in Normal Homeostasis and Cancer

MCL-1 possesses multiple functions in cells. On the outer mitochondrial membrane (OMM) MCL-1 inhibits cell death, similar to other anti-apoptotic BCL-2 family members. When targeted to the mitochondrial matrix (Matrix) the amino-terminal truncated MCL-1 also stimulates mitochondrial function including promoting normal ATP production, efficient oxidative phosphorylation, and reduced production of reactive oxygen species. These two separable functions may play critical roles in promoting normal and cancer cell survival. (a) In normal stem cells, it is possible that the homeostatic control on self-renewal is regulated primarily by MCL-1 OMM anti-apoptotic activity. In contrast, the proliferation and differentiation of stem cells into progenitors and terminally differentiated lineages may require efficient energy production promoted by the truncated MCL-1 targeted to the matrix. Lastly, proper homeostasis of terminally differentiated cells is likely controlled primarily by MCL-1 OMM's anti-apoptotic activity. (b) Cancer cells often have violated cellular checkpoints and become “addicted” to anti-apoptotic BCL-2 family members to counter the increased amounts of pro-apoptotic molecules expressed. Therefore, one prediction is that tumor cells may be highly dependent on MCL-1 OMM's anti-apoptotic function to “soak up” the pro-apoptotic expression and therefore inhibit the death of the malignant cell. However, cancer cells often proliferate rapidly and in addition to requiring a constant supply of ATP, they depend on mitochondrial byproducts as a source of macromolecular synthesis. MCL-1's matrix function may be necessary to help provide cancer cells with the building blocks to sustain rapid proliferation. Therefore, MCL-1's functional roles at the OMM and matrix may synergize to inhibit cell death and to promote cellular proliferation.