Mitochondrial Quality Control: Role in Cardiac Models of Lethal Ischemia-Reperfusion Injury

Figures

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  Figure 1. Myocardial ischemia-reperfusion injury. Schematic representation of myocardial cell death as a function of increasing duration of ischemia. In the absence of reperfusion, all cardiomyocytes will die: i.e., ~100% of cells are irreversibly injured (red curve). In theory, timely reintroduction of blood flow would salvage all remaining, previously ischemic cardiomyocytes (dotted line). However, reintroduction of blood flow paradoxically kills (rather than rescues) a population of previously ischemic myocytes—the phenomenon of ‘lethal ischemia-reperfusion injury’ (black curve). Adapted from reference [14].

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  Figure 2. Cellular consequences of ischemia-reperfusion in cardiomyocytes. Under conditions of ischemia (left), mitochondria are depolarized (i.e., ΔΨm is decreased) and ATP stores are depleted. This is accompanied by acidosis secondary to lactate accumulation, and an increase in intracellular calcium concentration. However, the OMM remains intact and the mPTP remains closed. Reintroduction of oxygen (right), results in the raid normalization of pH and increase in ΔΨm, and precipitates multiple deleterious sequelae including generation of ROS, exacerbated calcium overload, disruption of the OMM and opening of the mPTP. OMM = outer mitochondrial membrane; IMM = inner mitochondrial membrane; MOMP = mitochondrial outer membrane permeabilization; mPTP = mitochondrial permeability transition pore; ΔΨm = mitochondrial membrane potential; ROS = reactive oxygen species. Adapted from reference [12].

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  Figure 3. Mitochondrial morphosis under physiologic conditions. The dynamic fission-fusion balance occurs under steady-state conditions to promote mitochondrial biogenesis and/or culling of dysfunctional mitochondria by mitophagy. DRP1-mediated fission at the outer mitochondrial membrane reportedly occurs through interaction with cognate adapter proteins (Mff, Fis1, MiD49/51) at specific ER-contact foci. Transient cycling of DRP1 to these foci is suggested to maintain the fission-fusion balance. Dysfunctional mitochondrial segments are represented in blue, viable mitochondria represented in purple. OPA1 = optic atrophy protein-1; DRP1 = Dynamin related protein-1; Mfn 1/2 = mitofusins 1 & 2.

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  Figure 4. Mitochondrial morphosis under pathologic conditions. Ischemia-reperfusion is associated with an increase in DRP1-mediated fission, mitochondrial outer membrane permeabilization (MOMP) and the release of apoptogenic species into the cytoplasm. Degradation of OPA1 oligomers (achieved via stress-associated OMA1-mediated proteolytic cleavage of OPA1) disrupts cristae architecture, dissociating cytochrome c from within the cristae folds. MOMP is proposed to be a consequence of interaction of DRP1 with Bax/Bak oligomers at the outer membrane, and is considered to be a lethal event. Dysfunctional mitochondrial segments are represented in blue, viable mitochondria represented in purple. OPA1 = optic atrophy protein-1; DRP1 = dynamin related protein-1; Mfn 1/2 = mitofusins 1 & 2; MOMP = mitochondrial outer membrane permeabilization.

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  Figure 5. Example of OPA1 expression in whole cell lysates obtained from HL-1 cardiomyocytes under normoxic conditions and following simulated ischemia-reperfusion. HL-1 cardiomyocytes display five distinct OPA1 forms (bands a–e: 75–100 kDa), including two long (L) forms (bands a,b) and three short (S) forms (bands c–e). Ischemia-reperfusion is associated with the reduced expression of L-OPA1 bands due to OMA1-mediated cleavage of OPA1 and an attendant increase in expression of S-OPA1. S-IR = simulated ischemia-reperfusion.

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  Figure 6. Mitophagic elimination of dysfunctional mitochondria during ischemia-reperfusion. Mitophagy is achieved via four distinct pathways: (A) Detection of dysfunctional mitochondria through PINK1/Parkin recruitment, BNIP3/Nix homodimerization/activation, FUNDC1 activation, and externalization of cardiolipin. (B) Segregation of dysfunctional mitochondria through DRP1-dependent fission and disruption of fusion machinery. (C) Recognition of the dysfunctional mitochondria via LC3-binding domain interactions with the phagophore. (D) Degradation of the sequestered mitochondria by acid hydrolase enzymes following lysosomal fusion. Dysfunctional mitochondrial segments are represented in blue, viable mitochondria represented in purple. PGAM5 = positive regulator of FUNDC1; PINK1 = PTEN-induced kinase; BNIP3 = Bcl-2 adenovirus E1B 19-kDa-interacting protein-3; Mfn 1/2 = Mitofusins 1 & 2; DRP1 = dynamin related protein-1; LC3 = light chain-3 protein; ROS = reactive oxygen species.