CAV3 alleviates diabetic cardiomyopathy via inhibiting NDUFA10-mediated mitochondrial dysfunction.

BACKGROUND: The progression of diabetic cardiomyopathy (DCM) is noticeably influenced by mitochondrial dysfunction. Variants of caveolin 3 (CAV3) play important roles in cardiovascular diseases. However, the potential roles of CAV3 in mitochondrial function in DCM and the related mechanisms have not yet been elucidated. METHODS: Cardiomyocytes were cultured under high-glucose and high-fat (HGHF) conditions in vitro, and db/db mice were employed as a diabetes model in vivo. To investigate the role of CAV3 in DCM and to elucidate the molecular mechanisms underlying its involvement in mitochondrial function, we conducted Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis and functional experiments. RESULTS: Our findings demonstrated significant downregulation of CAV3 in the cardiac tissue of db/db mice, which was found to be associated with cardiomyocyte apoptosis in DCM. Importantly, cardiac-specific overexpression of CAV3 effectively inhibited the progression of DCM, as it protected against cardiac dysfunction and cardiac remodeling associated by alleviating cardiomyocyte mitochondrial dysfunction. Furthermore, mass spectrometry analysis and immunoprecipitation assays indicated that CAV3 interacted with NDUFA10, a subunit of mitochondrial complex I. CAV3 overexpression reduced the degradation of lysosomal pathway in NDUFA10, restored the activity of mitochondrial complex I and improved mitochondrial function. Finally, our study demonstrated that CAV3 overexpression restored mitochondrial function and subsequently alleviated DCM partially through NDUFA10. CONCLUSIONS: The current study provides evidence that CAV3 expression is significantly downregulated in DCM. Upregulation of CAV3 interacts with NDUFA10, inhibits the degradation of lysosomal pathway in NDUFA10, a subunit of mitochondrial complex I, restores the activity of mitochondrial complex I, ameliorates mitochondrial dysfunction, and thereby protects against DCM. These findings indicate that targeting CAV3 may be a promising approach for the treatment of DCM.

An Exploration of the Coherent Effects between METTL3 and NDUFA10 on Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized primarily by a decline in cognitive function. However, the etiopathogenesis of AD is unclear. N6-methyladenosine (m6A) is abundant in the brain, and it is interesting to explore the relationship between m6A and AD causes. In this paper, the gene expression of METTL3 and NDUFA10 were found to correlate with the Mini-mental State Examination (MMSE), which is a clinical indicator of the degree of dementia. METTL3 is involved in post-transcriptional methylation and the formation of m6A. NDUFA10 encodes the protein with NADH dehydrogenase activity and oxidoreductase activity in the mitochondrial electron transport chain. The following three characteristics were observed in this paper: 1. The lower the expression level of NDUFA10, the smaller the MMSE, and the higher the degree of dementia. 2. If the expression level of METTL3 dropped below its threshold, the patient would have a risk of AD with a probability close to 100%, suggesting a basic necessity for m6A to protect mRNA. 3. The lower the expression levels of both METTL3 and NDUFA10, the more likely the patient would suffer from AD, implying the coherence between METTL3 and NDUFA10. Regarding the above discovery, the following hypothesis is presented: METTL3 expression level is downregulated, then the m6A modification level of NDUFA10 mRNA is also decreased, thereby reducing the expression level of NDUFA10-encoded protein. Furthermore, the abnormal expression of NDUFA10 contributes to the assembly disorder of mitochondrial complex I and affects the process of the electron respiratory chain, with the consequent development of AD. In addition, to confirm the above conclusions, the AI Ant Colony Algorithm was improved to be more suitable for discovering the characteristics of AD data, and the SVM diagnostic model was applied to mine the coherent effects on AD between METTL3 and NDUFA10. In conclusion, our findings suggest that dysregulated m6A leads to altered expression of its target genes, thereby affecting AD's development.

Benzo[a]pyrene inhibits testosterone biosynthesis via NDUFA10-mediated mitochondrial compromise in mouse Leydig cells: Integrating experimental and in silico toxicological approaches.

Benzo[a]pyrene (B[a]P), a representative of polycyclic aromatic hydrocarbons (PAHs), is ubiquitously spread in the environment and showing deleterious impacts on male steroidogenesis, including testosterone synthesis disorder. However, the precise mechanisms involved in B[a]P-induced steroidogenesis perturbation remains obscure. In the present study, we integrated in vivo tests, transcriptome profiling, in vitro assays, and conjoint in silico toxicological approaches to delineate the detailed mechanisms. In mouse models, we observed that B[a]P administration remarkably inhibited testosterone synthesis accompanied by ultrastructural impairments of mitochondria and mitophagosome formation in mouse Leydig cells. Transcriptome profiling showed that B[a]P down-regulated the expression of Ndufa9, Ndufa6, Ndufa10, and Ndufa5 in mouse testes, which are identified as critical genes involved in the assembly and functionality of mitochondrial complex I. In the in vitro tests, the bioactive B[a]P metabolite BPDE induced perturbation of testosterone synthesis by NDUFA10-mediated mitochondrial impairment, which was further exacerbated by mitophagy in TM3 Leydig cells. The findings of in silico toxicological analyses were highly consistent with the experimental observations and further unveiled that B[a]P/BPDE-involved PPARα activation could serve as a molecular initiating event to trigger the decline in Ndufa10 expression and testosterone synthesis. Overall, we have shown the first evidence that mitochondrial compromise in Leydig cells is the extremely crucial target in B[a]P-induced steroidogenesis perturbation.

Widening the Heterogeneity of Leigh Syndrome: Clinical, Biochemical, and Neuroradiologic Features in a Patient Harboring a NDUFA10 Mutation.

Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder, characterized by a wide clinical and genetic heterogeneity, and is the most frequent disorder of mitochondrial energy production in children. Beside its great variability in clinical, biochemical, and genetic features, LS is pathologically uniformly characterized by multifocal bilateral and symmetric spongiform degeneration of the basal ganglia, brainstem, thalamus, cerebellum, spinal cord, and optic nerves. Isolated complex I deficiency is the most common defect identified in Leigh syndrome. In 2011, the first child with a mutation of NDUFA10 gene, coding for an accessory subunits of complex I, was described. Here, we present an additional description of a child with Leigh syndrome harboring a homozygous mutation in NDUFA10, providing insights in clinical, biochemical, and neuroradiologic features for future earlier recognition.