Regulation of mitochondrial nutrient and energy metabolism by BCL-2 family proteins

Abstract

Cells have evolved a highly integrated network of mechanisms to coordinate cellular survival/death, proliferation, differentiation, and repair with metabolic states. It is, therefore, not surprising that proteins with canonical roles in cell death/survival also modulate nutrient and energy metabolism and vice versa. The finding that many BCL-2 (B cell lymphoma 2) proteins reside at mitochondria or can translocate to this organelle has long motivated investigation into their involvement in normal mitochondrial physiology and metabolism. These endeavors have led to the discovery of homeostatic roles for BCL-2 proteins beyond apoptosis. Here, we predominantly focus on recent findings that link select BCL-2 proteins to carbon substrate utilization at the level of mitochondrial fuel choice, electron transport, and metabolite import independent of their cell death regulatory function.

The Role of BCL-2 Family Members in Acute Kidney Injury

“…54 Although seemingly at variance with one another, these hypotheses share a single important feature: that bax/bak insertion into the outer mitochondrial membrane represents a complex dance in which both the actor (the BCL-2 member) and recipient (the outer lipid membrane) affect the outcome of bax/bak membrane insertion that releases apoptogenic substances including cytochrome c, AIF, SMAC, diabalo, and the endonucleases that contribute to apoptotic morphology. 4,55 The notion that bax and bak also have "respectable mitochondrial functions" in maintaining the health of their potential victims is growing. Double knockout of bax and bak impairs the mitochondrial protein import mechanism that participates in mitochondrial biogenesis.…”

“…4 Specific BCL-2 proteins regulate carbon substrate use by activating a "fuel switch" that determines which intracellular substrate is favored. 4 At first, it seems odd that BCL-2 proteins are engaged intimately in cell metabolism; however, this family possesses "all "all the right stuff"; a close physical association with mitochondria, the powerhouse of aerobic adenosine triphosphate production, and the ability to reversibly insert into and coalesce within the outer (and likely the inner) mitochondrial membranes, the same location used for processing mitochondrial substrates. In addition to their effects on energy metabolism, select BCL-2 proteins regulate calcium homeostasis, DNA repair, and cell-cycle checkpoints.…”

“…Thus, BCL-2 proteins possess both a dark side as cell death regulators and a "lighter side" that includes active participation in daily housekeeping functions that maintain cell health. Recent reviews have described a diverse and expanding range of BCL-2 family functions far beyond their service as the "executioners of cell death" [4][5][6][7] and are summarized briefly ( Table 2). This review discusses the role of BCL-2 proteins in acute kidney diseases including ischemia, nephrotoxin exposure, and other renal insults including acute glomerulonephritis.…”

Poly(ADP-ribosylation) and neurodegenerative disorders

“…10 sometimes opposite functions (Rolland and Conradt, 2010;Giménez-Cassina and Danial, 2015;Lopez and Tait, 2015); given the crucial role of these proteins in apoptosis, their expression in neurodegenerative disorders has been addressed, showing often a deregulation of anti-apoptotic factors (reviewed in Anilkumar and Prehn, 2014).…”

Exploring the role of C5a-C5aR1 signalling in development through pluripotent stem cell modelling

“…Interestingly, the bcl-2 family of proteins have now been identified as regulators of energy metabolism independent of their apoptotic functions. In hepatocytes and beta islet cells, bad activates glucokinase to increase glycolysis, whilst bcl-2 and mcl-1 proteins have been shown to increase mitochondrial respiration and energy production (Giménez-Cassina and Danial 2015). C5a is known to modulate the activity of bcl-2 family proteins, however, to date this has only been explored in terms of canonical bcl-2 signalling, with an influence on cell metabolism largely unexplored (Perianayagam et al 2004;Perianayagam et al 2006;Lalli et al 2008).…”