Calpains, mitochondria, and apoptosis

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.

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

“…Calpain deficiencies as well as its over-activation are linked to a variety of diseases and pathological consequences (21). Because of their multifaceted nature, they control various irreversible signaling events and biological functions in the cell such as endothelial cell adhesion, differentiation, migration, proliferation, cell cycle control, cytoskeletal remodeling, embryonic development, and vesicular trafficking (12)(13)(14)(22)(23)(24). Our studies support a relationship between calpains and microvascular permeability at the level of the BBB.…”

“…Calpain-1 (also known as -calpain) and calpain-2 (also known as m-calpain) are predominantly expressed in the central and peripheral nervous systems (14,15). Calpain-1 is activated under low calcium concentrations (3-50 M), whereas calpain-2 is activated only under high concentrations (400 -800 M) of calcium in the cell (23,24).…”

“…Intracellular calcium levels and the endogenous inhibitor of calpains, namely calpastatin, tightly regulate calpain levels endogenously (9,13). Calpains-1 and -2 are the predominant calpains in the central nervous system (14,15). An increased calpain activity was observed following TBI in laboratory rodents (16,17) and human patients (12).…”

<i>CAPN10</i> SNP43 G&gt;A gene polymorphism and type 2 diabetes mellitus in the Asian population: a meta-analysis of 9353 participants

“…1, the effect size was heterogeneous among the studies (P heterogeneity =0.02) which indicated members in the CAPN family so far. The CAPN is classified into three types as typical CAPN (CAPN1, 2, 3, 8a, 9, 11, 12 and 13), CAPN subunits (CAPN4, and 14), and non-typical CAPN (CAPN5, 6, 7, 8b, 10, and 15) [31].…”

Mitochondrial Transcription Factor A's role in heart failure.

“…In mitochondrial decline, calpain 1 increases; it cleaves apoptosis inducibility factor (AIF), which is then translocated to the nucleus, inducing cell death (Cao et al 2007;Nath et al 2000;Smith and Schnellmann 2012a). Calpain X is a Ca 2+ -induced mitochondrial protease and a necessity for functional mitochondrial activity.…”