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Mitochondria-associated programmed cell death as a therapeutic target for age-related disease.

ABSTRACT: Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerative, cardiovascular and metabolic diseases. Thus, mitochondrion-associated programmed cell death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli and that maintain cellular homeostasis via mitohormesis, the mitochondrial unfolded protein response, and mitophagy. The review also presents details on various forms of mitochondria-associated programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis, and highlights their involvement in age-related disease pathogenesis, collectively suggesting therapeutic directions for further research.

SUBMITTER: Nguyen TT

PROVIDER: S-EPMC10474116 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Mitochondria-associated programmed cell death as a therapeutic target for age-related disease.

Nguyen Thanh T TT Wei Shibo S Nguyen Thu Ha TH Jo Yunju Y Zhang Yan Y Park Wonyoung W Gariani Karim K Oh Chang-Myung CM Kim Hyeon Ho HH Ha Ki-Tae KT Park Kyu Sang KS Park Raekil R Lee In-Kyu IK Shong Minho M Houtkooper Riekelt H RH Ryu Dongryeol D

Experimental & molecular medicine 20230823 8

Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerat ...[more]

PMID: 37612409

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Project description:BackgroundMultiple myeloma (MM) is a hematological malignancy characterized by the abnormal proliferation of plasma cells. Mitochondrial dysfunction and dysregulated programmed cell death (PCD) pathways have been implicated in MM pathogenesis. However, the precise roles of mitochondria-related genes (MRGs) and PCD-related genes (PCDRGs) in MM prognosis remain unclear.MethodsTranscriptomic data from MM patients and healthy controls were analyzed to identify differentially expressed genes (DEGs). Candidate genes were selected by intersecting DEGs with curated lists of MRGs and PCDRGs. Univariate Cox, least absolute shrinkage and selection operator (LASSO), multivariate Cox, and stepwise regression analyses identified prognostic genes among the candidates. A risk model was constructed from these genes, and patients were stratified into high- and low-risk groups for survival analysis. Independent prognostic factors were incorporated into a nomogram to predict MM patient outcomes. Model performance was evaluated using calibration curves, receiver operating characteristic (ROC) analysis, and decision curve analysis (DCA). Finally, associations between prognostic genes and immune cell infiltration/drug responses were explored.Results2,192 DEGs were detected between MM and control samples. 30 candidate genes were identified at the intersection of DEGs, 1,136 MRGs, and 1,548 PCDRGs. TRIAP1, TOMM7, PINK1, CHCHD10, PPIF, BCL2L1, and NDUFA13 were selected as prognostic genes. The risk model stratified patients into high- and low-risk groups with significantly different survival probabilities. Age, gender, ISS stage, and risk score were independent prognostic factors. The nomogram displayed good calibration and discriminative ability (AUC) in predicting survival, with clinical utility demonstrated by DCA. 9 immune cell types showed differential infiltration between MM and controls, with significant associations to risk scores and specific prognostic genes. 57 drugs, including nelarabine and vorinostat, were predicted to interact with the prognostic genes. Ultimately, qPCR in clinical samples from MM patients and healthy donors validated the expression levels of the seven key prognostic genes, corroborating the bioinformatic findings.ConclusionSeven genes (TRIAP1, TOMM7, PINK1, CHCHD10, PPIF, BCL2L1, NDUFA13) involved in mitochondrial function and PCD pathways were identified as prognostic markers in MM. These findings provide insights into MM biology and prognosis, highlighting potential therapeutic targets.

Project description:BackgroundTuberculosis (TB) is the deadliest communicable disease in the world with the exception of the ongoing COVID-19 pandemic. Programmed cell death (PCD) patterns play key roles in the development and progression of many disease states such that they may offer value as effective biomarkers or therapeutic targets that can aid in identifying and treating TB patients.Materials and methodsThe Gene Expression Omnibus (GEO) was used to gather TB-related datasets after which immune cell profiles in these data were analyzed to examine the potential TB-related loss of immune homeostasis. Profiling of differentially expressed PCD-related genes was performed, after which candidate hub PCD-associated genes were selected via a machine learning approach. TB patients were then stratified into two subsets based on the expression of PCD-related genes via consensus clustering. The potential roles of these PCD-associated genes in other TB-related diseases were further examined.ResultsIn total, 14 PCD-related differentially expressed genes (DEGs) were identified and highly expressed in TB patient samples and significantly correlated with the abundance of many immune cell types. Machine learning algorithms enabled the selection of seven hub PCD-related genes that were used to establish PCD-associated patient subgroups, followed by the validation of these subgroups in independent datasets. These findings, together with GSVA results, indicated that immune-related pathways were significantly enriched in TB patients exhibiting high levels of PCD-related gene expression, whereas metabolic pathways were significantly enriched in the other patient group. Single cell RNA-seq (scRNA-seq) further highlighted significant differences in the immune status of these different TB patient samples. Furthermore, we used CMap to predict five potential drugs for TB-related diseases.ConclusionThese results highlight clear enrichment of PCD-related gene expression in TB patients and suggest that this PCD activity is closely associated with immune cell abundance. This thus indicates that PCD may play a role in TB progression through the induction or dysregulation of an immune response. These findings provide a foundation for further research aimed at clarifying the molecular drivers of TB, the selection of appropriate diagnostic biomarkers, and the design of novel therapeutic interventions aimed at treating this deadly infectious disease.

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Mitochondria-associated programmed cell death as a therapeutic target for age-related disease.

Publications

Mitochondria-associated programmed cell death as a therapeutic target for age-related disease.

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