Aug 2026· Ageing Research Reviews· pp.
103312
· 0 citations· 195 references
Medicine
TL;DR
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.
Abstract
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.
The ability of AD treatments targeting classic pathological proteins to achieve meaningful clinical outcomes has been severely limited, shifting attention to the earlier upstream pathways that drive disease progression. Increasing evidence indicates that synaptic mitochondrial dysfunction is an early pathological event that directly contributes to synaptic loss and cognitive decline. This review focuses on how four interrelated pathologies—disrupted energy metabolism, calcium overload, imbalanced mitochondrial fission/fusion, and defective autophagy—converge to impair synaptic function and plasticity. Emerging therapeutic strategies aimed at protecting and restoring synaptic mitochondrial health, including mitochondria-targeted antioxidants, metabolic modulators, calcium signaling inhibitors, dynamics regulators, and autophagy inducers, are also examined. A central focus of the review is clinical translation: we summarize the preclinical evidence and critically evaluate major obstacles such as the lack of synapse-specific biomarkers, challenges in blood–brain barrier penetration and targeted delivery, and substantial patient heterogeneity. Rather than proposing a fully defined translational framework, we highlight the essential requirements for building one, centered on synaptic mitochondrial bioenergetics and quality control. Specifically, early and accurate biomarkers must be developed, patients should be stratified promptly, and rational combination therapies with complementary mechanisms need to be implemented. This organelle-centered perspective will clarify AD pathogenesis and help guide the development of next-generation neuroprotective therapies.
Unknown authors· Frontiers in Pharmacology· 0 citations
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
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.
L. Elabbasy· Current opinion in pharmacol...· 0 citations
This integrated framework reframes PD as a disorder of impaired cellular maintenance rather than solely a consequence of late-stage degenerative processes, and provides a translational shift from mechanism-based biomarkers to early detection of mitochondrial failure and supports therapeutic strategies aimed at restoring mitochondrial function and resilience.
Oscar Arias-Carrión, Magdalena Guerra-Crespo, L. O. Soto-Rojas et al.· Frontiers in Pharmacology· 0 citations
Several neurodevelopmental disorders and neurodegenerative diseases share common pathogenic mechanisms that unfold across the lifespan, blurring the distinction between the two nosological entities. Environmental factors, particularly those shaping metabolic health during critical developmental time windows, have emerged as key modulators of long-term brain liabilities. This review critically evaluates the experimental, epidemiological, and mechanistic evidence linking early-life metabolic and environmental insults with the establishment of latent vulnerability. We propose that this status may remain clinically silent for decades until activated by aging and cumulative stressors, ultimately leading to neurodegeneration. Specifically, we analyze how early metabolic alterations disrupt mitochondrial function, redox signaling, synaptogenesis, and glial programming, particularly in microglia, thereby shaping long-term neuroinflammatory tone and dysfunctional neural circuit maturation. The review highlights the role of the α7 nicotinic acetylcholine receptor (α7nAChR) as a strategic molecular bridge onto which metabolic and inflammatory signals converge. We further discuss how early dysregulatory stressors manifest later in life as dysmetabolism, vascular impairment, and defective energy sensing, all of which accelerate neurodegenerative pathophysiological processes. This life-course perspective reframes these disorders as a continuum and highlights critical prophylactic and/or therapeutic opportunities through early nutritional, metabolic, and environmental interventions.
Unknown authors· Frontiers in Neurology· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
