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Review
. 2012 Oct 1;96(1):32-7.
doi: 10.1093/cvr/cvs163. Epub 2012 May 11.

Calpains, mitochondria, and apoptosis

Matthew A Smith  1 , Rick G Schnellmann
Affiliations
Review

Calpains, mitochondria, and apoptosis

Matthew A Smith et al. Cardiovasc Res. .

Abstract

Mitochondrial activity is critical for efficient function of the cardiovascular system. In response to cardiovascular injury, mitochondrial dysfunction occurs and can lead to apoptosis and necrosis. Calpains are a 15-member family of Ca(2+)-activated cysteine proteases localized to the cytosol and mitochondria, and several have been shown to regulate apoptosis and necrosis. For example, in endothelial cells, Ca(2+) overload causes mitochondrial calpain 1 cleavage of the Na(+)/Ca(2+) exchanger leading to mitochondrial Ca(2+) accumulation. Also, activated calpain 1 cleaves Bid, inducing cytochrome c release and apoptosis. In renal cells, calpains 1 and 2 promote apoptosis and necrosis by cleaving cytoskeletal proteins, which increases plasma membrane permeability and cleavage of caspases. Calpain 10 cleaves electron transport chain proteins, causing decreased mitochondrial respiration and excessive activation, or inhibition of calpain 10 activity induces mitochondrial dysfunction and apoptosis. In cardiomyocytes, calpain 1 activates caspase 3 and poly-ADP ribose polymerase during tumour necrosis factor-α-induced apoptosis, and calpain 1 cleaves apoptosis-inducing factor after Ca(2+) overload. Many of these observations have been elucidated with calpain inhibitors, but most calpain inhibitors are not specific for calpains or a specific calpain family member, creating more questions. The following review will discuss how calpains affect mitochondrial function and apoptosis within the cardiovascular system.

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Figures

Figure 1
Figure 1
Diagram of a typical calpain, an atypical calpain, and small calpain subunit detailing different structural features. *Ca2+-binding sites. #Phosphorylation sites. CHN represents the Cys/His/Asn catalytic triad that is conserved throughout the family. Modified from Goll et al.
Figure 2
Figure 2
Diagram of the domain structure of calpastatin with a consensus sequence for subdomain B. *PKA phosphorylation site. Modified from Wendt et al.
Figure 3
Figure 3
Diagram of the possible effects of calpains on the mitochondria. Calpain 10 cleaves electron transport chain proteins, calpain 1 cleaves BH3-interacting domain death agonist (Bid), AIF,, and NCX, and calpain 2 cleaves voltage-dependent anion channel (VDAC).
See this image and copyright information in PMC

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