Cyclophilin D-mediated Mitochondrial Permeability Transition Regulates Mitochondrial Function

Abstract

Background: Mitochondria are multifunctional organelles, which participate in biochemical processes. Mitochondria acts as primary energy producers and biosynthetic centers of cells, which are involved in oxidative stress responses and cell signaling transduction. Among numerous potential mechanisms of mitochondrial dysfunction, the opening of the mitochondrial permeability transition pore (mPTP) is a major determinant of mitochondrial dysfunction to induce cellular damage or death. A plenty of studies have provided evidence that the abnormal opening of mPTP induces the loss of mitochondrial membrane potential, the impairment calcium homeostasis and the decrease of ATP production. Cyclophilin D (CypD), localized in the mitochondrial transition pore, is a mitochondrial chaperone that has been regarded as a prominent mediator of mPTP. Methods: This review describes the relationship between CypD, mPTP, and CypD-mPTP inhibitors through systematic investigation of recent relevant literature. Results: Here, we have highlighted that inhibiting the activity of CypD protects models of some diseases, including ischaemia/reperfusion injury (IRI), neurodegenerative disorders and so on. Knockdown studies have demonstrated that CypD possibly is mediated by its peptidyl-prolyl cis-trans isomerase activity, while the primary targets of CypD remain obscure. The target of CypD-mPTP inhibitor can alleviate mPTP opening-induced cell death. The present review is focused on the role of CypD as a prominent mediator of the mPTP, further providing insight into the physiological function of mPTP and its regulation by CypD. Conclusion: Blocking the opening of mPTP by inhibiting CypD might be a new promising approach for suppressing cell death, which will suggest novel therapeutic approaches for mitochondria-related diseases.

Homozygous CNP Mutation and Neurodegeneration in Weimaraners: Myelin Abnormalities and Accumulation of Lipofuscin-like Inclusions

“…However, studies indicate that is involved in regulating the functioning of the mitochondrial transition pore [29,38]. Abnormal regulation of the mitochondrial transition pore can result in cell damage or death [39][40][41][42]. Thus, deficiency in CNP protein would be predicted to alter both myelin structure and mitochondrial function.…”

Non-coding RNA and reprogrammed mitochondrial metabolism in genitourinary cancer

“…An antisense mtcciSCAR from the locus Cytochrome c oxidase 2 (COX2) was found to bind directly to the adenosine triphosphate synthase 5 beta ( Hyttinen et al, 2023 ). The interaction of ATP5B and mtcciSCAR blocks mitochondrial permeability transition pore (mPTP), and therefore reduces mitochondrial ROS ( Zhou et al, 2023 ). Another highly expressed mtcciRNA, mtcciCOX2, was found in chronic lymphocytic leukemia patients ( Wu et al, 2020a ; Zhao et al, 2020 ).…”

Broadening Horizons: Exploring mtDAMPs as a Mechanism and Potential Intervention Target in Cardiovascular Diseases

“…Conversely, the role of mtDNA in cardiac inflammation in these models remains unclear [95]. Ablation of cyclophilin D (CypD) inhibits mitochondrial permeability transition (MPT), which is responsible for mtDNA release and protects against ischemia/reperfusion injury [96]. The mechanism remains elusive, except for the inhibition of necrotic cell death.…”