Mitochondrial resilience: a convergent framework for pathogenesis and neuroprotection in Parkinson’s disease

Genetic and epigenetic complexity of Parkinson's disease: From dopamine pathways to estrogen interplay.

Mitochondrial Metabolism and Calcium Handling in Parkinson’s Disease hiPSC-derived Astrocytes

Astrocyte-specific mitochondrial dysfunctions and calcium dysregulation are identified as key features of LRRK2- and PRKN-related pathology, providing new insights into how glial metabolic alterations contribute to neurodegeneration in PD.

Mitochondrial ecosystem restoration in Alzheimer’s disease: from mechanisms to multi-target therapeutic strategies

Alzheimer’s disease (AD), the most prevalent cause of dementia, lacks definitive cures despite decades of research focused on amyloid-beta (Aβ) and tau pathologies. Emerging evidence positions mitochondrial dysfunction not merely as a downstream consequence, but as the epicenter linking aging, metabolic failure, and neuroinflammation in AD pathogenesis. This study synthesizes the latest advances in mitochondrial-targeted therapies, framing them within a “Mitochondrial Ecological Restoration” perspective. I analyze the molecular mechanisms by which mitochondrial-targeted therapies modulate oxidative stress, mitochondrial dynamics, mitophagy and neuroinflammation, and evaluate their translational potential. Accumulating evidence indicates that strategies ranging from antioxidants (e.g., MitoQ) to mitophagy enhancement (e.g., Spautin-1) and biogenesis activation (e.g., PGC-1α Activator) have demonstrated efficacy in preclinical models. These interventions theoretically interrupt the pathological cycle between proteotoxicity and bioenergetic crisis. While challenges in blood-brain barrier (BBB) penetration and target specificity persist, the field is shifting from single-target scavenging to combinatorial ecosystem repair. Future success will require precise delivery systems, early biomarkers, and a paradigm shift toward treating the neuron as a metabolic ecosystem, though substantial translational challenges remain.

Translational Insights into α-Synuclein Aggregation and Proteostasis Dysfunction in Parkinson’s Disease

Role of STX1A in Parkinson's disease: evidence, mechanistic hypotheses, and translational perspectives.

The biomarker and therapeutic potential of STX1A remains preliminary because diagnostic performance, disease specificity, longitudinal stability, and causal relevance have not been adequately validated and future studies using cell-type-specific STX1A manipulation, rescue experiments, electrophysiology, and multicenter longitudinal cohorts are required to define the biological and clinical significance of STX1A in PD.

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.