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Inhibition of the ubiquitous calpains protects complex I activity and enables improved mitophagy in hearts following ischemia-reperfusion.

08:00 EDT 14th August 2019 | BioPortfolio

Summary of "Inhibition of the ubiquitous calpains protects complex I activity and enables improved mitophagy in hearts following ischemia-reperfusion."

Activation of calpain1 (CPN1) and calpain2 (CPN2) contributes to cardiac injury during ischemia (ISC) and reperfusion (REP). Complex I activity is decreased in heart mitochondria following ISC-REP. CPN1 and CPN2 are ubiquitous calpains that exist in both cytosol (cs-CPN1&2) and mitochondria (mit-CPN1&2). Recent work shows that the complex I subunit (NDUFS7) is a potential substrate of the mit-CPN1. We asked if ISC-REP led to decreased complex I activity via proteolysis of the NDUFS7 subunit via activation of mit-CPN1&2. Activation of cs-CPN1&2 decreases mitophagy in hepatocytes following ISC-REP. We asked if activation of cs-CPN1&2 impaired mitophagy in the heart following ISC-REP. Buffer-perfused rat hearts underwent 25 min. global ISC and 30 min. REP. MDL-28170 (MDL, 10 µM) was used to inhibit CPN1&2. Cytosol, subsarcolemmal mitochondria (SSM), and interfibrillar mitochondria (IFM) were isolated at the end of heart perfusion. Cardiac ISC-REP led to decreased complex I activity with a decrease in the content of NDUFS7 in both SSM and IFM. ISC-REP also resulted in a decrease in cytosolic beclin1 content, a key component of the autophagy pathway required to form autophagosomes. MDL treatment protected the contents of cytosolic beclin1 and mitochondrial NDUFS7 in hearts following ISC-REP. These results support that activation of both cytosolic and mitochondrial calpains impairs mitochondria during cardiac ISC-REP. Mitochondria localized calpains impair complex I via cleavage of a key subunit. Activation of cytosolic calpains contributes to mitochondrial dysfunction by impairing removal of the impaired mitochondria through depletion of a key component of the mitophagy process.

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Name: American journal of physiology. Cell physiology
ISSN: 1522-1563
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