Mitochondrial Dysfunction in Alzheimer's Disease: Beyond Energy Failure Toward a Pathogenic Nexus

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Mitochondrial dysfunction is an early and central event in Alzheimer's disease (AD) pathophysiology.
• Beyond energy failure, it involves complex organelle homeostasis perturbations, acting as both a target and amplifier of neurodegenerative processes.
• This review synthesizes mechanistic roles and therapeutic implications of mitochondrial dysfunction in AD, highlighting recent advances.

Purpose of the Study:

• To provide a comprehensive synthesis of the mechanistic roles of mitochondrial dysfunction in Alzheimer's disease.
• To explore the therapeutic implications and emerging paradigms of mitochondrial involvement in AD.
• To underscore mitochondria as integrative nodes in AD onset, progression, and biomarker discovery.

Main Methods:

• Critical evaluation of literature from molecular, cellular, and systems-level studies.
• Inclusion of data from postmortem brain tissue, transgenic models, and patient-derived cells.
• Focus on key domains: bioenergetic collapse, redox imbalance, mitochondrial dynamics, Aβ and tau interactions, calcium dysregulation, apoptosis, MAMs, UPRmt, and mitonuclear communication.

Main Results:

• Alzheimer's disease exhibits widespread mitochondrial abnormalities: impaired oxidative phosphorylation, increased ROS, disrupted fission/fusion, defective mitophagy, and abnormal calcium buffering.
• Amyloid-beta (Aβ) and tau directly accumulate in mitochondria, disrupting protein import, respiratory chain integrity, and transport.
• These dysfunctions activate caspase-mediated apoptotic pathways, leading to synaptic loss and neuronal death.

Conclusions:

• Mitochondria are a mechanistic nexus in AD, linking pathological triggers to neurodegeneration.
• Therapeutic strategies include antioxidants, NAD+ precursors, mitophagy modulators, and MAM-targeted approaches.
• Mitochondrial biomarkers (circulating mtDNA, cytochrome c, neuroimaging) are emerging for early diagnosis and monitoring; precision mitochondrial medicine offers transformative potential for AD management.