The nuanced role of mitochondrial ROS in modulating aging and aging hallmarks

The organellar biology of aging: A mitochondrial vantage

Mitochondria in health and disease: cellular powerhouses, signaling centers, and drivers of dysfunction

Although the mitochondria are known as the cellular powerhouse, their function is beyond energy generation. These organelles regulate cellular metabolism, yet maintains a tightly regulated reactive oxygen species (ROS) generation and optimal redox state. In addition, mitochondria serve as mediators of physiological and pathological processes, such as maintenance of calcium balance, and control of apoptosis and mitophagy. All these make the mitochondria a major factor in both cellular and organismal regulation. However, mitochondria dysfunction may occur through many processes, including genetic mutations, increased production of ROS, metabolic failure from impaired electron transport chain activity, and dysregulated dynamics or mitophagy. Several self-perpetuating damages accumulate from these processes and influence clinical pathologies, such as aging, metabolic syndrome, cancer, neurodegeneration, and reproductive disorders. Recent studies demonstrate promising therapeutic targets for mitochondrial dysfunction. Examples include targeted antioxidants, such as MitoQ and SkQ1, to selectively neutralize mitochondrial ROS, pharmacological modulators to enhance mitochondrial biogenesis and to restore NAD + homeostasis via PGC-1α activation, gene-editing technologies, such as mitoTALENs and mtZFNs to selectively eliminate pathogenic mitochondrial DNA mutations, and mitochondrial transplantation as a new technique to replace damaged organelles. Together, these novel approaches highlight the need for research in mitochondrial function to change the therapeutic landscape in the management of mitochondrial dysfunction-associated diseases.

Mitochondrial Permeability Transition Regulators As Emerging Therapeutic Targets in Aging and Neurodegeneration: Recent Insights

Mitochondrial respiratory supercomplexes associated with longevity in mammals

Because of population aging and morbidity expansion, extending healthspan has become a global challenge and it is required to elucidate molecular mechanisms underlying aging and age-related diseases. Mitochondrial dysfunction is a hallmark of aging, characterized by impaired oxidative phosphorylation, increased production of reactive oxygen species (ROS), and metabolic imbalance. Therefore, maintaining mitochondrial homeostasis is essential for healthspan. Mitochondrial respiratory chain complexes organize into higher-order assemblies known as supercomplexes (SCs), which enable to efficient energy or ATP production with repressed ROS generation. Notably, the assembly and stability of these SCs likely decline in aged mammals. In addition, factors such as COX7RP/SCAF1 and mitochondrial lipid cardiolipin have emerged as key regulators of SC assembly. In this review, we summarize the molecular assembly, physiological roles, and longevity implications of SC in healthy mammals. We further discuss emerging evidence supporting SC modulation as a potential strategy for promoting healthy aging.

Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Therapeutic Advances.

Neurodegenerative diseases associated with ageing are characterized by progressive neuronal dysfunction and loss, yet effective disease-modifying therapies remain elusive. Increasing evidence indicates that mitochondrial dysfunction is not merely a downstream consequence of neurodegeneration but represents an early and active driver of disease initiation and progression. This review addresses this critical gap by establishing an integrated framework that systematically connects mechanistic insights with translational applications. We demonstrate that mitochondrial impairment precedes classical neuropathological hallmarks, thereby positioning mitochondrial dysfunction as a primary driver rather than a secondary consequence of neurodegeneration. Through comprehensive analysis of disease-specific molecular signatures, we reveal how distinct mitochondrial regulatory failures converge on common downstream pathways: bioenergetic collapse through respiratory chain complex deficiencies, oxidative stress amplification via mitochondrial DNA damage and reactive oxygen species overproduction, calcium dysregulation, and compromised quality control through impaired mitophagy. Critically, we integrate emerging evidence demonstrating bidirectional crosstalk between mitochondrial dysfunction and neuroinflammation, establishing a self-perpetuating pathogenic loop that accelerates disease progression. By synthesizing advances in multi-omics profiling, single-cell resolution analyses, and in vivo imaging biomarkers, we provide a systems-level perspective that transcends reductionist single-pathway models. Furthermore, we critically evaluate the translational landscape of mitochondria-targeted interventions, encompassing pharmacological agents with defined molecular targets, gene therapy approaches addressing mitochondrial DNA mutations, and lifestyle modifications promoting systemic metabolic resilience. Our comparative analysis reveals complementary mechanistic profiles and practical limitations across these modalities, supporting an integrated therapeutic paradigm that combines broad metabolic optimization with precision targeting of specific mitochondrial defects.

To longevity and beyond: a systems view of aging and stress resilience.