Mitochondrial Dynamism and Cardiac Fate

to the functioning of the mitochondrial matrix electron transport pathway enzymes that generate ATP. The OMM also protects the cell by compartmentalizing soluble pro-apoptotic mitochondrial factors, such as cytochrome c. Accordingly, the OMM barrier is stabilized by anti-apoptotic Bcl2-factors such as Bcl-xL, and destabilized by pro-apoptotic Bcl2-proteins such as Bax, Bak, Nix, and Bnip3. Loss of OMM integrity (ie, “OMM permeabilization”) is the initial step in mitochondrial pathway apoptosis. If mitochondria are gateways to cell death, then these gateways are constantly changing size, shape, and location via organelle transport, fission, and fusion. This is “mitochondrial dynamics”. The molecular mechanisms of mitochondrial fission and fusion are understood and have recently been reviewed in depth.15,16 The OMM is also the physical and biochemical nexus for mitochondrial fusion/fission. Mitochondrial fusion mediated by mitofusin (Mfn) 1 and Mfn2, and fission mediated by dynamin-related protein 1 (Drp1), occur with far less frequency in normal adult cardiac myocytes than in the more commonly studied fibroblasts,17 but recent work has uncovered essential roles for Mfn-mediated mitochondrial fusion and mitochondria-SR tethering in cardiac homeostasis.18–20 Conversely, pathologic mitochondrial fragmentation is observed in cardiomyocyte apoptosis and HF,21 although it is unclear if mitochondrial fission is an important effector of, or just a collateral event in, apoptosis.22,23 Because of the need for large amounts of ATP to fuel excitation-contraction coupling (~6 kg/day), hearts have the greatest density of mitochondria of any organ. It is axiomatic that mitochondrial health is essential to general health,24 and past research has focused on the cardiac consequences of altered itochondria are cellular powerhouses, but are also “gateways to apoptosis”. 1,2 Accordingly, multiple research studies over the past decade have defined context-specific molecular effectors of mitochondrial-mediated programmed cardiomyocyte death. My laboratory contributed to this area by developing the first in vivo mouse model to prove that cardiomyocyte apoptosis is sufficient to induce heart failure (HF). 3 Subsequently, 2 Bcl-2 family “mitochondrial death” proteins that are the genetically programmed effectors of cardiomyocyte apoptosis (Nix in cardiac hypertrophy and Bnip3 in cardiac ischemia) were identified.4–7 These 2 transcriptionally regulated proteins localize primarily to the outer mitochondrial membranes (OMM) where they facilitate Bax/Bak-mediated OMM permeabilization, cytochrome c release, and activation of caspase-dependent apoptosis signaling.8 Recently, added and unexpected functions of these mitochondrial death proteins were uncovered. Nix localizes (in addition to mitochondria) to endoplasmic/sarcoplasmic reticulum (ER/SR) where it regulates SR-mitochondrial calcium crosstalk that opens mitochondrial permeability transition pores (MPTPs),9,10 inducing a non-apoptotic form of programmed cell death, designated “programmed necrosis”. 11,12 Nix also plays an important role in mitochondrial quality control, targeting dysfunctional mitochondria for mitophagic elimination.13,14 Thus, “pro-apoptotic” mitochondrial Bcl2-family proteins are multi-taskers that also modulate programmed necrosis and mitophagy. It is at the OMM where mitochondrial and extra-mitochondrial factors interface and interact to determine mitochondrial integrity, and hence cell fate. The normal cytosolic/organelle OMM barrier maintains a protective internal milieu essential M