Hippo pathway deficiency reverses systolic heart failure after infarction. Leach JP et al. (2017) Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs, such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in mortality. The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration, is upregulated in human heart failure. Here we show that deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls. Using translating ribosomal affinity purification, we isolate cardiomyocyte-specific translating messenger RNA. Hippo-deficient cardiomyocytes have increased expression of proliferative genes and stress response genes, such as the mitochondrial quality control gene, Park2. Genetic studies indicate that Park2 is essential for heart repair, suggesting a requirement for mitochondrial quality control in regenerating myocardium. Gene therapy with a virus encoding Salv short hairpin RNA improves heart function when delivered at the time of infarct or after ischaemic heart failure following myocardial infarction was established. Our findings indicate that the failing heart has a previously unrecognized reparative capacity involving more than cardiomyocyte renewal.//////////////////
NCBI Summary:
The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]
General function
Enzyme
Comment
Cellular localization
Comment
Ovarian function
Follicle atresia
Comment
FSH protects mouse granulosa cells from oxidative damage by repressing mitophagy. Shen M et al. (2016) Oxidative stress has been implicated in triggering granulosa cell (GC) death during follicular atresia. Recent studies suggested that follicle-stimulating hormone (FSH) has a pivotal role in protecting GCs from oxidative injury, although the exact mechanism remains largely unknown. Here, we report that FSH promotes GC survival by inhibiting oxidative stress-induced mitophagy. The loss of GC viability caused by oxidative stress was significantly reduced after FSH treatment, which was correlated with impaired activation of mitophagy upon oxidative stress. Compared with FSH treatment, blocking mitophagy displayed approximate preventive effect on oxidative stress-induced GC death, but FSH did not further restore viability of cells pretreated with mitophagy inhibitor. Importantly, FSH suppressed the induction of serine/threonine kinase PINK1 during oxidative stress. This inhibited the mitochondrial translocation of the E3 ligase Parkin, which is required for the subsequent clearance of mitochondria, and ultimately cell death via mitophagy. In addition, knocking down PINK1 using RNAi confirmed the role of the FSH-PINK1-Parkin-mitophagy pathway in regulating GC survival under oxidative conditions. These findings introduce a novel physiological function of FSH in protecting GCs against oxidative damage by targeting PINK1-Parkin-mediated mitophagy.//////////////////
Expression regulated by
FSH
Comment
FSH prevents porcine granulosa cells from hypoxia-induced apoptosis via activating mitophagy through the HIF-1α-PINK1-Parkin pathway. Li C et al. (2020) In developing follicles, the granulosa cells (GCs) live in a hypoxic environment due to the devoid of blood supply. Upon hypoxic conditions, several types of mammalian cells have been reported to undergo apoptosis. Follicle-stimulating hormone (FSH) is known as the primary survival factor for antral follicles by preventing GCs apoptosis. Mitophagy is a type of organelle-specific autophagy that removes damaged or stressed mitochondria to maintain cellular health. This study provides the first evidence suggesting that FSH-mediated mitophagy protected porcine GCs from hypoxia-induced apoptosis. Our data showed that the GCs apoptosis caused by mitochondrial pathway upon hypoxia stress was markedly attenuated after FSH treatment, which was correlated with enhanced activation of mitophagy. Interestingly, FSH also stimulated mitochondrial biogenesis as suggested by increased expression of mitochondrial transcription factor A and nuclear respiratory factor 1 during hypoxia exposure. Notably, the protein level of hypoxia inducible factor-1α (HIF-1α) was significantly increased in hypoxic GCs following FSH treatment, accompanied by elevated mitophagic activity and dampened apoptotic signaling. Blocking HIF-1α inhibited mitophagy and restored hypoxia-induced apoptosis despite FSH treatment. Importantly, FSH promoted the expression of serine/threonine kinase PTEN induced putative kinase 1 (PINK1) and the E3 ligase Parkin during hypoxia stress through a HIF-1α dependent manner. This induced the mitophagic clearance of damaged mitochondria, hence inhibiting apoptosis by reducing cytochrome c releasing. The inhibition of HIF-1α and/or PINK1 using inhibitor or RNAi further confirmed the role of the FSH-HIF-1α-PINK1-Parkin-mitophagy axis in suppressing GC apoptosis under hypoxic conditions. These findings highlight a novel function of FSH in preserving GCs viability against hypoxic damage by activating HIF-1α-PINK1-Parkin-mediated mitophagy.//////////////////
Ovarian localization
Granulosa
Comment
Follicle stages
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: type: null mutation fertility: unknown Comment: Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. Palacino JJ et al. (2004) Loss-of-function mutations in parkin are the predominant cause of familial Parkinson's disease. We previously reported that parkin-/- mice exhibit nigrostriatal deficits in the absence of nigral degeneration. Parkin has been shown to function as an E3 ubiquitin ligase. Loss of parkin function, therefore, has been hypothesized to cause nigral degeneration via an aberrant accumulation of its substrates. Here we employed a proteomic approach to determine whether loss of parkin function results in alterations in abundance and/or modification of proteins in the ventral midbrain of parkin-/- mice. Two-dimensional gel electrophoresis followed by mass spectrometry revealed decreased abundance of a number of proteins involved in mitochondrial function or oxidative stress. Consistent with reductions in several subunits of complexes I and IV, functional assays showed reductions in respiratory capacity of striatal mitochondria isolated from parkin-/- mice. Electron microscopic analysis revealed no gross morphological abnormalities in striatal mitochondria of parkin-/- mice. In addition, parkin-/- mice showed a delayed rate of weight gain, suggesting broader metabolic abnormalities. Accompanying these deficits in mitochondrial function, parkin-/- mice also exhibited decreased levels of proteins involved in protection from oxidative stress. Consistent with these findings, parkin-/- mice showed decreased serum antioxidant capacity and increased protein and lipid peroxidation. The combination of proteomic, genetic, and physiological analyses reveal an essential role for parkin in the regulation of mitochondrial function and provide the first direct evidence of mitochondrial dysfunction and oxidative damage in the absence of nigral degeneration in a genetic mouse model of Parkinson's disease.//////////////////