Search Results (130)

Ischemic stroke induces complex neuroinflammatory cascades, where microglial autophagy and mitophagy serve dual roles in both injury amplification and tissue repair. This scoping review synthesized current evidence on their regulatory mechanisms and therapeutic implications. Literature was identified via PubMed and Embase, yielding 79 records, from which 39 original research articles and 13 review papers were included after eligibility screening. Search terms included “microglia,” “autophagy,” and “ischemic stroke.” Protective autophagy was frequently associated with AMPK activation, mTOR inhibition, and mitophagy pathways such as PINK1/Parkin and BNIP3/NIX, facilitating mitochondrial clearance, M2 polarization, and anti-inflammatory signaling. Therapeutic agents such as rapamycin, Tat-Beclin 1, and Urolithin A consistently demonstrated neuroprotection in preclinical stroke models. In contrast, excessive or prolonged autophagic activation was linked to inflammasome amplification, oxidative stress, and phagoptosis. Limited human studies reported associations between elevated serum ATG5 levels or ATG7 polymorphisms and worse clinical outcomes, suggesting preliminary translational relevance. These findings support the potential of phase-specific modulation of microglial autophagy as a therapeutic avenue for stroke, although further validation in human models and development of autophagy biomarkers are needed for clinical application. Full article

Rhabdomyolysis is characterized by the breakdown of skeletal muscle tissue, frequently leading to acute kidney injury (AKI). Traditional conservative treatments have shown limited effectiveness in modifying the disease course, thereby necessitating targeted pharmacological approaches. Zileuton (Z), a selective inhibitor of 5-lipoxygenase (5-LOX), has demonstrated efficacy in enhancing renal function recovery in animal models of AKI induced by agents such as cisplatin, aminoglycosides, and polymyxins. The present study aimed to evaluate the therapeutic potential of a single dose of Z in mitigating rhabdomyolysis-induced AKI (RI-AKI) via modulation of myeloid-derived suppressor cells (MDSCs). Male C57BL/6 mice were assigned to four experimental groups: Sham (intraperitoneal administration of 0.9% saline), Z (single intraperitoneal injection of Z at 30 mg/kg body weight), glycerol (Gly; single intramuscular dose of 50% glycerol at 8 mL/kg), and glycerol plus Z (Z + Gly; concurrent administration of glycerol intramuscularly and Z intraperitoneally). Animals were sacrificed 24 h post-glycerol injection for analysis. Zileuton administration significantly improved renal function, as indicated by reductions in blood urea nitrogen (BUN) levels (129.7 ± 17.9 mg/dL in the Gly group versus 101.7 ± 6.8 mg/dL in the Z + Gly group, p < 0.05) and serum creatinine (Cr) levels (2.2 ± 0.3 mg/dL in the Gly group versus 0.9 ± 0.3 mg/dL in the Gly + Z group p < 0.05). Histopathological assessment revealed a marked decrease in tubular injury scores in the Z + Gly group compared to the Gly group. Molecular analyses demonstrated that Z treatment downregulated mRNA expression of macrophage-inducible C-type lectin (mincle) and associated macrophage infiltration-related factors, including Areg-1, Cx3cl1, and Cx3CR1, which were elevated 24 h following glycerol administration. Furthermore, the expression of NLRP-3, significantly upregulated post-glycerol injection, was attenuated by concurrent Z treatment. Markers of mitochondrial biogenesis, such as mitochondrial DNA (mtDNA), transcription factor A mitochondrial (TFAM), and carnitine palmitoyltransferase 1 alpha (CPT1α), were diminished 24 h after glycerol injection; however, their expression was restored upon simultaneous Z administration. Additionally, Z reduced protein levels of BNIP3, a marker of mitochondrial autophagy, while enhancing the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), suggesting that Z ameliorates RI-AKI severity through the regulation of mitochondrial quality control mechanisms. Zileuton also decreased infiltration of CD11b(+) Gr-1(+) MDSCs and downregulated mRNA levels of MDSC-associated markers, including transforming growth factor-beta (TGF-β), arginase-1 (Arg-1), inducible nitric oxide synthase (iNOS), and iron regulatory protein 4 (Irp4), in glycerol-injured kidneys relative to controls. These markers were elevated 24 h post-glycerol injection but were normalized following concurrent Z treatment. Collectively, these findings suggest that Zileuton confers reno-protective effects in a murine model of RI-AKI, potentially through modulation of mitochondrial dynamics and suppression of MDSC-mediated inflammatory pathways. Further research is warranted to elucidate the precise mechanisms by which Z regulates MDSCs and to assess its therapeutic potential in clinical contexts. Full article

Background: Astrocytes are not only structural cells but also play a pivotal role in neurogenesis and neuroprotection by secreting a variety of neurotrophic factors that support neuronal survival, growth, and repair. This study investigates the time-dependent responses of primary rat cortical astrocytes to oxygen–glucose deprivation (OGD) and evaluates the neuroprotective potential of astrocyte-conditioned medium (ACM). Methods: Primary rat cortical astrocytes and neurons were obtained from postnatal Sprague Dawley rat pups (P1–3) and embryos (E17–18), respectively. Astrocytes exposed to 6, 24, and 48 h of OGD (0.3% O₂) were assessed for viability, metabolic function, hypoxia-inducible factor 1 and its downstream genes expression. Results: While 6 h OGD upregulated protective genes such as Vegf, Glut1, and Pfkfb3 without cell loss, prolonged OGD, e.g., 24 or 48 h, led to significant astrocyte death and stress responses, including elevated LDH release, reduced mitochondrial activity, and increased expression of pro-apoptotic marker Bnip3. ACM from 6 h OGD-treated astrocytes significantly enhanced neuronal survival following 6 h OGD and 24 h reperfusion, preserving dendritic architecture, improving mitochondrial function, and reducing cell death. This protective effect was not observed with ACM from 24 h OGD astrocytes. Furthermore, 6 h OGD-ACM induced autophagy in neurons, as indicated by elevated LC3b-II and decreased p62 levels, suggesting autophagy as a key mechanism in ACM-mediated neuroprotection. Conclusions: These findings demonstrate that astrocytes exhibit adaptive, time-sensitive responses to ischemic stress and secrete soluble factors that can confer neuroprotection. This study highlights the therapeutic potential of targeting astrocyte-mediated signalling pathways to enhance neuronal survival following ischemic stroke. Full article

Nucleobase and nucleoside analogs are critical components of antimetabolite chemotherapy treatments used to disrupt DNA replication and induce apoptosis in rapidly proliferating cancer cells. However, the development of resistance to these agents remains a major clinical challenge. This review explores the epigenetic mechanisms that contribute to acquired chemoresistance, focusing on DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). These epigenetic alterations regulate key processes such as DNA repair, drug metabolism, cell transport, and autophagy, enabling cancer cells to survive and resist therapeutic pressure. We highlight how dysregulation of DNA methyltransferases (DNMTs) and histone acetyltransferases (HATs) modulates expression of transporters (e.g., hENT1, ABCB1), DNA repair enzymes (e.g., Polβ, BRCA1/2), and autophagy-related genes (e.g., CSNK2A1, BNIP3). Furthermore, emerging roles for long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in regulating nucleoside export and DNA damage response pathways underscore their relevance as therapeutic targets. The interplay of these epigenetic modifications drives resistance to agents such as gemcitabine and 5-fluorouracil across multiple tumor types. We also discuss recent progress in therapeutic interventions, including DNMT and HDAC inhibitors, RNA-based therapeutics, and CRISPR-based epigenome editing. Full article

In this study, we investigated the inhibitory effects of emodin on pyroptosis in rheumatoid arthritis (RA) synovial cells by modulating the HIF-1α/NLRP3 inflammasome pathway and mitochondrial autophagy. By employing a chemically induced hypoxia model with CoCl₂, we established experimental groups including normal control, model group, and emodin-treated groups at different concentrations (5 μM, 10 μM, and 20 μM). We optimized the CoCl₂ concentration via CCK-8 assay to ensure cell viability. ELISA, Western blotting, transmission electron microscopy, and immunofluorescence were employed to assess HIF-1α, IL-1β, and IL-18 levels, pyroptosis-related proteins, autophagy markers, and NLRP3 fluorescence intensity. Statistical analysis revealed that increased CoCl₂ concentrations led to a significant cell viability reduction (p < 0.05), with 300 μM CoCl₂ causing ~50% inhibition at 24 h. Transmission electron microscopy confirmed autophagosome formation in emodin-treated groups, while Western blotting showed dose-dependent downregulation of HIF-1α, NLRP3, BNIP3, and related proteins. Immunofluorescence revealed reduced NLRP3 fluorescence intensity with increasing emodin doses (p < 0.05), alongside dose-dependent cell viability recovery (p < 0.05). Our findings demonstrate that emodin alleviates RA synovitis through dual mechanisms: inhibition of mitochondrial autophagy to regulate the balance between mitochondrial autophagy and pyroptosis, and suppression of HIF-1α/NLRP3-mediated pyroptosis signaling, thereby reducing IL-1β and IL-18 release and inhibiting synovial cell proliferation. This study provides innovative approaches for targeted RA therapy. Full article

Given the escalating global temperatures and the consequent exacerbation of heat stress, dietary interventions have emerged as a promising therapeutic strategy. The gastrointestinal tract, being exquisitely sensitive to thermal challenges, revealing the underlying mechanisms of intestinal cell injury under high temperature, is essential for developing strategies to prevent heat stress. Here, we integrated metabolomic and transcriptomic analyses to investigate the metabolic and genetic changes in murine intestinal cells in response to different levels of heat stress. The results identified the PI3k-Akt-FoxO pathway as the major heat stress regulatory pathway Kin MODE-K cells. The possible regulatory mechanism is to reduce the expression of the FoxO gene through the downstream phosphorylation of PI3K under the stimulation of growth factors such as INS, IGF1 and TGF-β. Then, through acetylation modification, it regulates the expression of the Gadd45 gene, promotes the expression of p19 and BNIP3 genes, and inhibits the expression of the ATG8 gene, thus inducing apoptosis to remove cells that cannot be repaired. It also promotes cyclinB, PLK, and Bcl-6 gene expression in cells surrounding apoptotic cells to inhibit apoptosis. It promotes the expression of RAG1/2 to enhance cellular immunity and regulates the G6pc gene to maintain the homeostasis of glycogen metabolism and glucose under heat stress. Our findings provide a basis for the regulation of intestinal cell damage due to heat stress through dietary interventions. Full article

Cardiac adaptations induced by aerobic exercise have been shown to reduce the risk of cardiovascular disease, and the autonomic nervous system is closely associated with the development of cardiovascular disease. Aerobic exercise intervention has been shown to enhance cardiac function and mitigate myocardial fibrosis and hypertrophy in heart failure mice. Further insights reveal that cardiomyocytes experiencing chronic heart failure undergo modifications in their lipidomic profile, including remodeling of multiple myocardial membrane phospholipids. Notably, there is a decrease in the total content of cardiolipin, as well as in the levels of total lysolipid CL and the CL (22:6). These alterations disrupt mitochondrial quality control processes, leading to abnormal expressions of proteins such as Drp1, MFN2, OPA1, and BNIP3, thereby resulting in a disrupted mitochondrial dynamic network. Whereas aerobic exercise ameliorated mitochondrial damage to a large extent by activating parasympathetic nerves, this beneficial effect was accomplished by modulating myocardial membrane phospholipid remodeling and restoring the mitochondrial dynamic network. In conclusion, aerobic exercise activated the parasympathetic state in mice and attenuated lipid peroxidation and oxidative stress injury, thereby maintaining mitochondrial dynamic homeostasis and improving cardiac function. Full article

Mitochondrial dysfunction is a pivotal driver in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and congenital anomalies of the kidney and urinary tract (CAKUT). The kidneys, second only to the heart in mitochondrial density, rely on oxidative phosphorylation to meet the high ATP demands of solute reabsorption and filtration. Disrupted mitochondrial dynamics, such as excessive fission mediated by Drp1, exacerbate tubular apoptosis and inflammation in AKI models like ischemia–reperfusion injury. In CKD, persistent mitochondrial dysfunction drives oxidative stress, fibrosis, and metabolic reprogramming, with epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) regulating genes critical for mitochondrial homeostasis, such as PMPCB and TFAM. Epigenetic dysregulation also impacts mitochondrial–ER crosstalk, influencing calcium signaling and autophagy in renal pathology. Mitophagy, the selective clearance of damaged mitochondria, plays a dual role in kidney disease. While PINK1/Parkin-mediated mitophagy protects against cisplatin-induced AKI by preventing mitochondrial fragmentation and apoptosis, its dysregulation contributes to fibrosis and CKD progression. For instance, macrophage-specific loss of mitophagy regulators like MFN2 amplifies ROS production and fibrotic responses. Conversely, BNIP3/NIX-dependent mitophagy attenuates contrast-induced AKI by suppressing NLRP3 inflammasome activation. In diabetic nephropathy, impaired mitophagy correlates with declining eGFR and interstitial fibrosis, highlighting its diagnostic and therapeutic potential. Emerging therapeutic strategies target mitochondrial dysfunction through antioxidants (e.g., MitoQ, SS-31), mitophagy inducers (e.g., COPT nanoparticles), and mitochondrial transplantation, which mitigates AKI by restoring bioenergetics and modulating inflammatory pathways. Nanotechnology-enhanced drug delivery systems, such as curcumin-loaded nanoparticles, improve renal targeting and reduce oxidative stress. Epigenetic interventions, including PPAR-α agonists and KLF4 modulators, show promise in reversing metabolic reprogramming and fibrosis. These advances underscore mitochondria as central hubs in renal pathophysiology. Tailored interventions—ranging from Drp1 inhibition to mitochondrial transplantation—hold transformative potential to mitigate kidney injury and improve clinical outcomes. Additionally, dietary interventions and novel regulators such as adenogens are emerging as promising strategies to modulate mitochondrial function and attenuate kidney disease progression. Future research should address the gaps in understanding the role of mitophagy in CAKUT and optimize targeted delivery systems for precision therapies. Full article

Runs of homozygosity (ROHs) are continuous homozygous segments of genomes that can be used to infer the historical development of the population. ROH studies allow us to analyze the genetic structure of a population and identify signs of selection. The present study searched for ROH regions in the Faverolle chicken breed. DNA samples from modern individuals and museum Faverolle specimens were obtained and sent for whole-genome sequencing (WGS) with 30× coverage. The results were aligned to the reference genome and subjected to additional filtering. ROH segments were then analyzed using PLINK 1.9. As a result, 10 regions on GGA1, 2, 3, 4, and 13 were identified. A total of 19 genes associated with fat deposition and lipid metabolism (GBE1, CACNA2D1, STON1, PPP1R21, RPL21L1, ATP6V0E1, CREBRF, NKX2-2, COMMD1), fertility (LHCGR, GTF2A1L, SAMD5), muscle development and body weight (VGLL3, CACNA2D1, FOXN2, ERGIC1, RPL26L1), the shape and relative size of the skeleton (FAT4), and autophagy and apoptosis (BNIP1) were found. Developmental protein genes (PAX1, NKX2-2, NKX2-4, NKX2-5) formed a separate cluster. Probably, selection for the preservation of high flavor characteristics contributed to the consolidation of these ROH regions. The present research enhances our knowledge on the Faverolle breed’s genome and pinpoints their ROH segments that are also specific «selection traces». Full article

Diabetic retinopathy (DR) is a leading cause of visual impairment. To better understand the pathology, clinically relevant experimental models are needed. Widely used DR models (especially streptozotocin (STZ)-induced) require extended timeframes to reach DR phenotype endpoints and lack ischemic phenotypes, which are in contrast to the human condition. Unilateral common carotid artery occlusion (UCCAO) could provide a retinal ischemic insult. We explored the pathologic synergistic effects of UCCAO in STZ mice. STZ (90 mg/kg) was injected intraperitoneally into adult C57BL/6 mice for three days. Four weeks later, right UCCAO was performed. One week after UCCAO, retinal samples were stained with isolectin B4 to analyze cellular and vascular changes. Retinal samples were obtained one day and one week after UCCAO and quantitative PCR (qPCR) were performed to observe inflammatory and ischemic responses. Only the STZ UCCAO group showed increased inflammatory cells. STZ UCCAO retina demonstrated a significant difference in capillary and large vessel size compared to other groups. At one day and one week, there was a change in mRNA expressions in inflammatory genes Ccl2, Ccl12, Bnip3, Pdk1, Hsp25, and Vegfa in the STZ UCCAO group compared to other groups. Our model can serve as an accelerated DR model for studying inflammatory vascular changes. Full article

m⁶A methylation modification is an important genetic modification involved in biological processes such as sexual maturation, antibacterial, and antiviral in aquatic animals. However, few studies have been conducted in aquatic animals on the relationship between m⁶A methylation modification and autophagy-inflammation induced by lipid metabolism disorders. In the present study, a high-fat (HF) group and HF-MLP group (1 g mulberry leaf polysaccharides (MLPs)/1 kg HF diet) were set up. The mid-hind intestines of Megalobrama amblycephala juveniles from the two groups were collected for MeRIP-seq and RNA-seq after an 8-week feeding trial. The m⁶A peaks in the HF and HF-MLP groups were mainly enriched in the 3′ Untranslated Region (3′UTR), Stop codon, and coding sequence (CDS) region. Compared with the HF group, the m⁶A peaks in the HF-MLP group were shifted toward the 5′UTR region. ‘RRACH’ was the common m⁶A methylation motif in the HF and HF-MLP groups. Methyltransferase mettl14 and wtap expression in the intestines of the HF-MLP group were significantly higher compared with the HF group (p < 0.05). A total of 21 differentially expressed genes(DEGs) with different peaks were screened by the combined MeRIP-seq and RNA-seq analysis. Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis enriched BCL2 interacting protein 3 (bnip3) to autophagy–animal and mitophagy–animal signaling pathways, etc., and nucleotide-binding domain leucine-rich repeat protein 1 (nlrp1) was enriched to the Nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathway. Combined MeRIP-seq and RNA-seq analysis indicated that the expression pattern of bnip3 was hyper-up and that of nlrp1 was hyper-down. Gene Set Enrichment Analysis (GSEA) analysis confirmed that the intestinal genes of HF-MLP group positively regulate lysosomal and autophagy–animal signaling pathways. In the present study, we demonstrated that m⁶A methylation modification plays a role in regulating autophagy-inflammatory responses induced by HF diets by MLPs, and further explored the molecular mechanisms by which MLPs work from the epigenetic perspective. Full article

The therapeutic potential of presumed cardiac progenitor cells (CPCs) in heart regeneration has garnered significant interest, yet clinical trials have revealed limited efficacy due to challenges in cell survival, retention, and expansion. Priming CPCs to survive the hostile hypoxic environment may be key to enhancing their regenerative capacity. We demonstrate that microRNA-210 (miR-210), known for its role in hypoxic adaptation, significantly improves CPC survival by inhibiting apoptosis through the downregulation of Casp8ap2, a ~40% reduction in caspase activity, and a ~90% decrease in DNA fragmentation. Contrary to the expected induction of Bnip3-dependent mitophagy by hypoxia, miR-210 did not upregulate Bnip3, indicating a distinct anti-apoptotic mechanism. Instead, miR-210 reduced markers of mitophagy and increased mitochondrial biogenesis and oxidative metabolism, suggesting a role in metabolic reprogramming. Furthermore, miR-210 enhanced the secretion of paracrine growth factors from CPCs, with a ~1.6-fold increase in the release of stem cell factor and of insulin growth factor 1, which promoted in vitro endothelial cell proliferation and cardiomyocyte survival. These findings elucidate the multifaceted role of miR-210 in CPC biology and its potential to enhance cell-based therapies for myocardial repair by promoting cell survival, metabolic adaptation, and paracrine signalling. Full article

Cervical cancer is a leading cause of death in women globally. Systemic chemotherapy offers only limited therapeutic benefit for advanced-stage disease due to toxicity and drug resistance. ONC201 (also known as TIC10 or dordaviprone) is a TRAIL (TNF-Related Apoptosis-Inducing Ligand) and cIpP (caseinolytic protease) agonist currently in Phase II clinical trials for different types of cancer. In the present study, we investigated the anticancer potential of ONC201 in HPV-positive cervical cancer cell lines. ONC201 exerted significant cytotoxicity and inhibited the clonogenic potential of cervical cancer cells. It induced integrated stress response along with S/G2-M arrest and apoptosis in both cell lines. Yet, surprisingly, well-known targets of ONC201 viz. TRAIL, DR5 (death receptor 5) and cIpP were found to be upregulated only in HeLa but not in SiHa cells in response to ONC201 treatment. In addition, expression of BNIP3 and Beclin-1 (both involved in regulation of autophagy) increased in response to certain doses of ONC201. Furthermore, ONC201 exhibited synergism in combination with standard drugs against cervical cancer cells. This study provides a proof of concept for the anticancer activity of versatile drug ONC201 against cervical cancer cells and also delineates its mechanism of action. Full article

Fipronil (FPN), a widely used pesticide, is associated with significant immunotoxic effects, particularly impacting thymocyte survival and immune homeostasis. This study explores the mechanistic pathways underlying FPN-induced apoptosis and oxidative stress. Short-term FPN exposure (1–10 mg/kg) notably suppressed the expression of both anti-apoptotic (Bcl-2, Bcl-6, Mcl-1) and pro-apoptotic (Bnip3, Bim) genes in thymic tissues in vivo. Additionally, in isolated primary thymocytes, FPN directly decreased the expression of Bcl-2, Bcl-6, Mcl-1, and Bnip3 expression, coupled with a significant increase in pro-apoptotic Bim expression in a dose-dependent manner. FPN treatment directly led to elevated reactive oxygen species (ROS), lipid peroxidation, mitochondrial membrane depolarization, reduced cellular metabolic activity, and depleted intracellular calcium and glutathione (GSH) levels, indicating mitochondrial dysfunction and oxidative stress. Annexin V/PI staining confirmed that FPN induced late-stage apoptosis and necrosis in primary thymocytes. These findings elucidate the immunotoxic effects of FPN on thymocytes, highlighting its detrimental impact on immune system integrity, thymic development, and T cell maturation through oxidative damage and mitochondrial-mediated apoptosis. Full article

To explore the molecular mechanism of aerobic exercise to improve heart failure and to provide a theoretical basis and experimental reference for the treatment of heart failure. Nine-week-old male mice were used to establish a left ventricular pressure overload-induced heart failure model by transverse aortic constriction (TAC). The mice were randomly divided into four groups: a sham group (SHAM), heart failure group (HF), heart failure + SKQ1 group (HS) and heart failure + aerobic exercise group (HE). The mice in the HE group were subjected to moderate-intensity aerobic exercise interventions. The mitochondrion-targeting antioxidant (SKQ1) contains the lipophilic cation TPP, which targets scavenging mitochondrial ROS. The HS group was subjected to SKQ1 (100 nmol/kg/d) interventions, which were initiated 1 week after the surgery, and the interventions lasted 8 weeks. Cardiac function was assessed by ultrasound, cardiomyocyte size by H&E and WGA staining, myocardial fibrosis by Masson’s staining, and myocardial tissue oxidative stress and apoptosis by DHE and TUNEL fluorescence staining, respectively. Western blotting was used to detect the expression of mitochondrial quality control, inflammation, and apoptosis-related proteins. In the cellular level, an in vitro cellular model was established by isolating primary cardiomyocytes from neonatal mice (2–3 days) and intervening with Ang II (1 μM) to mimic heart failure. Oxidative stress and mitochondrial membrane potential were determined in the cardiomyocytes of each group by DHE and JC-1 staining, respectively. Myocardial fibrosis was increased significantly and cardiac function was reduced significantly in the heart failure mice. Aerobic exercise and SKQ1 intervention improved cardiac function and reduced myocardial hypertrophy and myocardial fibrosis in the heart failure mice significantly. Meanwhile, aerobic exercise and SKQ1 intervention reduced the number of DHE-positive particles (p < 0.01) and inhibited myocardial oxidative stress in the heart failure mice significantly. Aerobic exercise also reduced DRP1, Parkin, and BNIP3 protein expression (p < 0.05, p < 0.01), and increased OPA1 and PINK1 protein expression (p < 0.05, p < 0.01) significantly. Moreover, aerobic exercise and SKQ1 intervention decreased the number of TUNEL-positive particles and the expression of inflammation- and apoptosis-related proteins NLRP3, TXNIP, Caspase-1, IL-1β, BAX, BAK, and p53 significantly (p < 0.05, p < 0.01). In addition, the AMPK agonist AICAR and the mitochondria-targeted ROS scavenger (SKQ1) ameliorated AngII-induced mitochondrial fragmentation and decreased mitochondrial membrane potential in cardiomyocytes significantly. It was shown that inhibition of mitochondrial ROS by aerobic exercise, which in turn inhibits mitochondrial damage, improves mitochondrial quality control, and reduces myocardial inflammatory and apoptosis, may be an important molecular mechanism by which aerobic exercise exerts endogenous antioxidant protective effects to improve cardiac function. Full article