Aug 2026· Current opinion in pharmacology (Print)· Vol 90, pp.
102662
· 0 citations· 68 references
Medicine
TL;DR
This review focuses on the core mechanisms that link mitochondrial dysfunction to disease progression and the major barriers to translation, and examines biomarker development and the major barriers to translation.
Abstract
Mitochondrial dysfunction has emerged as a convergent pathogenic mechanism across inflammatory and degenerative disorders, functioning not as a passive consequence but as an active amplifier of tissue injury, immune dysregulation, and impaired repair. Consistently observed mitochondrial abnormalities include excessive reactive oxygen species production, impaired oxidative phosphorylation, defective mitophagy, altered fission-fusion dynamics, and release of mitochondrial danger-associated molecular patterns, particularly cell-free mitochondrial DNA (cf-mtDNA), which serves both as a proinflammatory mediator and a potential circulating biomarker of disease activity. These alterations create self-reinforcing networks in which mitochondrial stress promotes innate immune activation, sustains inflammatory signaling, and accelerates structural or functional decline in vulnerable tissues. Mitochondria-targeted pharmacology has expanded rapidly, encompassing organelle-directed antioxidants, modulators of mitochondrial quality control, biogenesis or metabolic enhancers, nano-enabled delivery platforms, and emerging mitochondrial replacement strategies. Despite strong mechanistic appeal and encouraging preclinical data, clinical translation remains limited by the absence of validated pharmacodynamic biomarkers, an incomplete understanding of disease endotypes, inconsistent tissue target engagement, delivery barriers to mitochondria-rich compartments, and poor predictive value of animal models for human disease biology. The cf-mtDNA and related mitochondrial signatures are increasingly attracting attention for patient stratification, phenotyping, and therapeutic monitoring, although assay standardization remains unresolved. This review focuses on the core mechanisms that link mitochondrial dysfunction to disease progression. It also examines biomarker development and the major barriers to translation. Emerging approaches such as nanotechnology and mitochondrial replacement are discussed as supplementary strategies, not as the main focus of the review.
Recent studies demonstrate promising therapeutic targets for mitochondrial dysfunction and highlight the need for research in mitochondrial function to change the therapeutic landscape in the management of mitochondrial dysfunction-associated diseases.
Olufemi Akintayo Akinkunmi, Feyikemi Funmilayo Araba, J. A. Chukwudebelu et al.· Frontiers in Cell and Develo...· 0 citations
Mitochondria serve as central hubs for cellular energy production, calcium homeostasis, and signal transduction, playing pivotal roles in maintaining cardiomyocyte viability and function. Mitochondrial dysfunction is closely implicated in the pathogenesis of various cardiovascular diseases, including myocardial ischemia-reperfusion injury, myocardial infarction, doxorubicin-induced cardiomyopathy, peripheral artery disease, and diabetic cardiomyopathy. Mitochondrial transplantation (MT) has emerged as a promising therapeutic strategy that involves delivering functional exogenous mitochondria to damaged tissues to restore bioenergetic capacity and promote cellular repair mechanisms. Preclinical studies across multiple animal models have demonstrated its efficacy in reducing infarct size, enhancing functional recovery, and modulating inflammatory responses. Current MT techniques encompass diverse approaches for mitochondrial isolation, storage, and delivery, with both direct injection and indirect transplantation methods under investigation. Despite encouraging results from early-phase clinical trials highlighting its safety and feasibility, significant translational challenges remain. These include unresolved mechanistic debates—such as whether benefits arise from direct mitochondrial integration or paracrine immunomodulation—as well as issues related to long-term safety, standardization of mitochondrial preparations, optimization of delivery routes, and the need for rigorous, large-scale randomized controlled trials. This review summarizes the current evidence, critically examines the opportunities and barriers in the field, and outlines key directions for future research to advance MT toward clinical application in cardiovascular medicine.
In renal cell carcinoma (RCC), alterations in cellular metabolism are a defining feature, among which impaired mitochondrial function stands out as a key factor influencing both tumor aggressiveness and patient responses to therapy. The aim of this review is to systematically synthesize current knowledge on the role of mitochondrial dysfunction in RCC pathogenesis and to explore emerging therapeutic strategies targeting mitochondrial vulnerabilities. This comprehensive analysis examines the integrated dysregulation of core mitochondrial processes—bioenergetic metabolism, organelle dynamics, programmed cell death pathways, redox homeostasis, and selective autophagy—in driving RCC pathogenesis. Our synthesis reveals how genetic drivers, molecular regulators, and microenvironmental cues converge to remodel mitochondrial function, creating both adaptive advantages and therapeutic vulnerabilities. A paradoxical duality emerges in mitochondrial biology: processes such as fission, mitophagy, and reactive oxygen species (ROS) generation can simultaneously support tumor adaptation while rendering cells susceptible to targeted interventions. We evaluate emerging therapeutic approaches directed at mitochondrial vulnerabilities, including metabolic inhibitors, nanoscale delivery systems, and phytochemical agents, while addressing current limitations in specificity and resistance mechanisms. Based on current preclinical evidence, this integrated perspective establishes mitochondrial dysfunction as a central determinant of RCC malignancy and suggests potential combinatorial strategies for precision oncology approaches that warrant further investigation.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Conventional downstream interventions targeting β-amyloid (Aβ) and tau proteins have repeatedly failed in clinical practice, and mitochondrial functional decline has been identified as the core upstream driver of AD pathogenesis. Focusing on the mitochondrial functional network as the core target, this paper systematically dissects the key molecular mechanisms of mitochondrial dysfunction during AD progression, including oxidative phosphorylation impairment, mitochondrial DNA (mtDNA) mutations and genetic defects, excessive reactive oxygen species (ROS) production, mitochondrial dynamics imbalance, mitophagy dysfunction, calcium homeostasis dysregulation, mitochondrial transport defects, and the bidirectional regulatory pathway of tau pathology, and elucidates the pathological network featured by cascade amplification and reciprocal regulation among these abnormal mechanisms. It also comprehensively summarizes mitochondria-targeted intervention strategies for AD, analyzes the research limitations in this field such as model heterogeneity, lack of specific biomarkers and inefficient drug delivery, and prospects future research directions by integrating cutting-edge technologies including cell reprogramming and artificial intelligence (AI). This study provides a novel interpretation of the aging-related pathogenic mechanisms of AD from a mitochondrial perspective, lays a theoretical foundation for the development of precise and efficient mitochondria-targeted therapeutic strategies for AD, and offers a new paradigm for breaking through the bottlenecks of clinical diagnosis and treatment of AD.
Unknown authors· Ageing Research Reviews· 0 citations
It is demonstrated that mitochondrial impairment precedes classical neuropathological hallmarks, thereby positioning mitochondrial dysfunction as a primary driver rather than a secondary consequence of neurodegeneration, and critically evaluates the translational landscape of mitochondria-targeted interventions.
Zhaomin Yao, Yangwa Wei, Weiming Xie et al.· Ageing Research Reviews· 0 citations
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