Association Between L-OPA1 Cleavage and Cardiac Dysfunction During Ischemia-Reperfusion Injury in Rats

Abstract

Background/Aims: Structural and functional alterations in mitochondria, particularly, the inner mitochondrial membrane (IMM) plays a critical role in mitochondria-mediated cell death in response to cardiac ischemia-reperfusion (IR) injury. The integrity of IMM can be affected by two potential intra-mitochondrial factors: i) mitochondrial matrix swelling, and ii) proteolytic cleavage of the long optic atrophy type 1 (L-OPA1), an IMM-localized dynamin-like GTPase engaged in the regulation of structural organization and integrity of the mitochondrial cristae. However, the relationship between these two factors in response to oxidative stress remains unclear. Here, we elucidated the effects of cardiac IR injury on L-OPA1 cleavage and OMA1 activity. Methods: Langendorff-mode perfused isolated rat hearts were subjected to 25-min of global ischemia followed by 90-min reperfusion in the presence or absence of XJB-5-131 (XJB, a mitochondria-targeting ROS scavenger) and sanglifehrin A (SfA, a permeability transition pore inhibitor). Results: XJB in combination with SfA increased post-ischemic recovery of cardiac function and reduced mitochondrial ROS production at 30- and 60-min reperfusion and affected mitochondrial swelling. L-OPA1 levels were reduced in IR hearts; however, neither XJB, SfA, and their combination prevented IR-induced reduction of L-OPA1 cleavage. Likewise, IR increased the OMA1 enzymatic activity, which remained unchanged in the presence of XJB and/or SfA. Conclusion: IR-induced cardiac and mitochondrial dysfunctions are associated with OMA1 activation and L-OPA1 cleavage. However, XJB, SfA, and their combination do not prevent these changes despite improved heart and mitochondria function, thus, suggesting that different mechanisms can be implicated in L-OPA1 processing in response to cardiac IR injury.

Mitochondrial Dysfunction in Cardiorenal Syndrome 3: Renocardiac Effect of Vitamin C

“…FIS1 overexpression was expected after renal insult, as mentioned by some reports [65], but FIS was unaltered in our model. Moreover, both OPA1 and Mfn2 were reported to be decreased regarding cardiovascular disease [55,[66][67][68][69], but in our study, both biomarkers were not altered in the nontreated vitamin C groups. Drp1 overexpression was also documented as a mediator of fragmentation in heart diseases and CRS [63,[70][71][72].…”

Elucidating the contribution of mitochondrial glutathione to ferroptosis in cardiomyocytes

“…All chemicals were handled with the appropriate personal protective equipment under the regulations established by the Biosafety and Biosecurity Committee of the UPR Medical Sciences Campus. Hearts were isolated from the rats and perfused according to the Langendorff-mode technique as described previously [ 22 ].…”

Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury

“…Moderately active OMA1 and YME1L maintain a steady-state balance between fusion and fission. Stress insults or metabolic cues can activate OMA1 or YME1L in RGCs ( Rodriguez-Graciani et al, 2020 ). During aging and in diseases, increased OPA1 processing limits the content of fusion-active L-OPA1 and triggers mitochondrial fragmentation ( Baburamani et al, 2015 ).…”