Mitochondrion最新文献

Temperature critically impacts ectotherm metabolism, notably mitochondrial respiration, enzyme activity, and ATP production. However, the effect of temperature on reactive oxygen species (ROS) production remains poorly understood in these organisms. Here, we investigated the thermal sensitivity of H₂O₂ production by isolated mitochondria from Drosophila melanogaster. We measured H₂O₂ emission rates at six temperatures (18-45 °C) during: (i) oxidative phosphorylation (OXPHOS) fueled by NADH-linked substrates feeding electrons into complex I (CI), as well as by FADH₂-linked substrates such as proline, succinate, and glycerol-3-phosphate (G3P); and (ii) during non-phosphorylating conditions with FADH₂-linked substrates as well as using defined substrate/inhibitor combinations such as pyruvate, malate and rotenone (P/M-driven), as well as supported by proline, succinate, and G3P when inhibitors are present. We calculated relative H₂O₂ emission rates and compared them with previously measured enzyme activities and oxygen consumption rates. Our results show marked thermal sensitivity of H₂O₂ emission during OXPHOS and when P/M-driven. At elevated temperatures, increased ROS production by NADH-linked substrates during OXPHOS coincided with a decline in CI-induced oxygen consumption capacity and pyruvate dehydrogenase (PDH) activity, indicating a dysfunction in NADH-producing and -consuming systems. In contrast, substrates feeding electrons into the Q pool via FADH₂ oxidation support respiration at high temperature decoupled from ROS production, suggesting a metabolic strategy to sustain respiration while limiting oxidative stress. These findings highlight that mitochondrial thermal sensitivity involves a complex regulation of ROS metabolism. Our study provides new insights into mitochondrial ROS dynamics and their implications for upper thermal tolerance in insects.

Friedreich's ataxia (FRDA) is a rare disease caused by deficiency of frataxin, a mitochondrial protein essential for iron-sulfur cluster assembly and iron homeostasis. In addition to neurological symptoms, cardiac dysfunction is common and represents a major cause of premature death in FRDA. Although iron overload has been suggested as a major player for FRDA-related cardiomyopathy, its underlying mechanisms remain unclear. Using heart-specific frataxin deficient mice, we observed that FRDA-related cardiac hypertrophy is accompanied by mitochondrial iron overload. Transmission electron microscopy (TEM) revealed iron aggregates within cardiac mitochondria, whose ultrastructure was severely altered. Along with the iron deposits and structural abnormalities, mitochondrial respiration was markedly impaired in FRDA hearts, despite the absence of increased oxidative stress. Notably, although dysfunctional mitochondria accumulate in parallel with enhanced mitochondrial biogenesis, the clearance of damaged or dysfunctional mitochondria (i.e., mitophagy) is disrupted, as evidenced by excessive accumulation of p62 and Parkin proteins. The lysosomal system, which plays a central role for mitochondrial turnover, appears to be dysregulated via the mTOR-TFEB axis. Hyperactivation mTOR inhibits lysosomal biogenesis and function, although lysosomal content remains unchanged. Collectively, our study provides mechanistic insight into the role of mitochondrial iron aggregates in the pathogenesis of FRDA-related cardiomyopathy and suggests a potential contribution of lysosomal dysfunction to impaired mitochondrial quality control in the context of cardiac frataxin deficiency.

In recent years, PANoptosis, as a novel form of cell death that integrates multiple cell death pathways, has progressively emerged as a cutting-edge research field in the study of cell death and immune regulation. PANoptosis, a recently proposed form of inflammatory programmed cell death, integrates features of pyroptosis, apoptosis, and necroptosis, while emphasizing their interplay. It is mediated by the PANoptosome and plays a pivotal role in infections, inflammation, tumors, and degenerative diseases. Recent studies have demonstrated that ROS serve as critical signaling molecules for PANoptosome assembly. Given that mitochondria constitute the primary intracellular source of ROS, this establishes a crucial link between mitochondrial and PANoptosis activation. Mitochondria sustain energy production, calcium homeostasis, and signaling but also contribute to immune responses and cell death. Oxidative stress, obesity, and environmental pollutants can induce mitochondrial dysfunction, manifested through impaired mitochondrial dynamics, which subsequently leads to excessive ROS production and mtDNA leakage. These pathological changes ultimately trigger PANoptosis activation. This review systematically summarizes how mitochondrial dysfunction triggers PANoptosis through mechanisms such as ROS accumulation, aberrant mitochondrial dynamics, and mtDNA leakage. Furthermore, it explores the implications of this process in traumatic brain injury, inflammatory diseases, ischemic disorders, and diseases induced by environmental toxins (e.g., microplastics and heavy metals). Understanding the interplay between mitochondria and PANoptosis may provide critical insights into the pathogenesis of inflammation-related diseases and offer novel mitochondria-targeted therapeutic strategies.

Prolonged cold ischemia-warm reperfusion (PCI/WR) of donor livers is an independent risk factor for primary nonfunction (PNF) after liver transplantation (LT). Previous studies have demonstrated that may be related to hepatocyte apoptosis mediated by the abnormal mitochondrial division. In the present study, we report that PCI/WR up-regulated apoptotic signals in donation after circulatory death (DCD) rat livers after 24 h of cold ischemia, increased the expression of PP2A, Drp1 and CHOP, and led to caspase-induced apoptosis. Downregulation of PP2A attenuated PCI/WR-induced hepatocyte injury, improved liver function, and decreased the expression of Drp1 and CHOP. In particular, okadaic acid (OA) inhibited the translocation of Drp1 to mitochondria and the release of Cyt c into the cytoplasm. Further investigation found that inhibiting mitochondrial division or ER-stress could slightly reverse the apoptosis rate induced by PCI/WR, while not affecting PP2A expression in vivo or in vitro. These observations indicated that PP2A involved in the regulation of hepatocyte apoptosis after prolonged cold storage, possibly through inhibiting the expression of Drp1 and CHOP, as well as Drp1 translocation. Our results provide evidence that PP2A could be a potential target for therapeutic intervention of DCD livers subjected to prolonged cold ischemia.