The novel cyclophilin-D-interacting protein FASTKD1 protects cells against oxidative stress-induced cell death

Abstract

Opening of the mitochondrial permeability transition (MPT) pore leads to necrotic cell death. Excluding cyclophilin D (CypD), the makeup of the MPT pore remains conjecture. The purpose of these experiments was to identify novel MPT modulators by analyzing proteins that associate with CypD. We identified Fas-activated serine/threonine phosphoprotein kinase domain-containing protein 1 (FASTKD1) as a novel CypD interactor. Overexpression of FASTKD1 protected mouse embryonic fibroblasts (MEFs) against oxidative stress-induced reactive oxygen species (ROS) production and cell death, whereas depletion of FASTKD1 sensitized them. However, manipulation of FASTKD1 levels had no effect on MPT responsiveness, Ca2+-induced cell death, or antioxidant capacity. Moreover, elevated FASTKD1 levels still protected against oxidative stress in CypD-deficient MEFs. FASTKD1 overexpression decreased Complex-I-dependent respiration and ΔΨm in MEFs, effects that were abrogated in CypD-null cells. Additionally, overexpression of FASTKD1 in MEFs induced mitochondrial fragmentation independent of CypD, activation of Drp1, and inhibition of autophagy/mitophagy, whereas knockdown of FASTKD1 had the opposite effect. Manipulation of FASTKD1 expression also modified oxidative stress-induced caspase-3 cleavage yet did not alter apoptotic death. Finally, the effects of FASTKD1 overexpression on oxidative stress-induced cell death and mitochondrial morphology were recapitulated in cultured cardiac myocytes. Together, these data indicate that FASTKD1 supports mitochondrial homeostasis and plays a critical protective role against oxidant-induced death.

Transcriptome comparisons detect new genes associated with apoptosis of cattle and buffaloes preantral follicles

“…FASTKD1 was shown to protect cells from oxidative stress-induced cell death and to suppress autophagy, whereas downregulation of FASTKD1 sensitized cells to cell death mechanisms [ 16 ]. Bcl-2-associated athanogene (BAG) family proteins interact with various partners included in modifying the proliferation/death balance, including the anti-apoptotic Bcl-2, and enhance its anti-apoptotic effects [ 17 ].…”

FASTK family of genes linked to cancer

“…FASTKD1 protects cells from oxidative stress and ROS induced cell death, the mechanism of which remains unknown. It also modulates mitochondrial dynamics in a CypD-independent manner, as well as autophagy/mitophagy and caspase-3 activation C [ 15 ]. Owing to this function, FASTKD1 was considered as a novel target for modulation of oxidative stress induced cell death and post-myocardial infarction healing [ 16 ].…”

Common protein-coding variants influence the racing phenotype in galloping racehorse breeds

“…The FASTKD1 and PPIG genes are also located in the region exhibiting the selection signal for G6PC2. The FAST kinase domains 1 protein, encoded by FASTKD1, supports mitochondrial homeostasis, and has a critical protective role against oxidant-induced cell death [98][99][100][101] . However, the strongest association in racing breeds was with the G6PC2 SNP and its wellestablished biological function in the regulation of glucose suggests that it could underpin the selection signal at this locus.…”