Mitochondrial Dynamics in Neurodegenerative Disease Mechanisms

Mitochondrial dynamics encompass the balanced processes of fission, fusion and organelle transport that sustain neuronal bioenergetics and quality control. In healthy neurons, continual cycles of fusion and fission regulate mitochondrial distribution along axons and dendrites, ensure efficient energy supply and facilitate removal of damaged fragments via mitophagy. In neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease, dysregulation of these dynamics precipitates bioenergetic deficits, calcium dyshomeostasis and heightened oxidative stress. Protein aggregates, notably α-synuclein and amyloid-β-tau species, interfere with key dynamin-related GTPases and tethering complexes at ER–mitochondria contact sites, provoking excessive fragmentation or impaired fusion. This imbalance amplifies mitochondrial DNA damage, disrupts axonal transport and compromises synaptic function. Emerging evidence highlights how defective clearance of dysfunctional mitochondria, via both canonical PINK1–Parkin and alternative mitophagy pathways, exacerbates neuronal vulnerability. Unravelling these interconnected pathways has uncovered novel targets for therapeutic intervention aimed at restoring organelle homeostasis and preventing progressive neuronal loss.

Research from Nature Portfolio

Recent studies have elucidated the mechanism by which oligomeric α-synuclein interacts with mitochondrial ATP synthase to induce selective oxidation of the β subunit, triggering the opening of the permeability transition pore and subsequent mitochondrial swelling in Parkinson’s disease models. Investigations using patient-derived induced pluripotent stem cell neurons bearing SNCA triplication revealed that elevated α-synuclein oligomers disrupt complex I-dependent respiration and calcium handling, thereby linking protein aggregation directly to organelle failure and neuronal death.

Mitochondrial Dynamics in Neurodegenerative Disease Mechanisms publication trend

The graph below shows the total number of articles in mitochondrial dynamics in neurodegenerative disease mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Mitochondrial dynamics: The processes of organelle fission, fusion and trafficking that regulate mitochondrial shape, distribution and function.

Mitophagy: Selective degradation of damaged mitochondria via the autophagy-lysosome pathway to maintain cellular homeostasis.

Permeability transition pore: A proteinaceous channel in the inner mitochondrial membrane whose opening under stress leads to loss of membrane potential and onset of cell death.

α-synuclein oligomer: Small aggregated assemblies of α-synuclein protein linked to mitochondrial impairment and neuronal toxicity.

ULK1-Rab9 pathway: An alternative mitophagy initiation route that operates independently of the canonical PINK1–Parkin mechanism.

Reactive oxygen species: Highly reactive oxygen-containing molecules that can damage proteins, lipids and DNA, contributing to neurodegeneration.

References

1. α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease. Nature Communications (2018).
2. Soluble, Prefibrillar α-Synuclein Oligomers Promote Complex I-dependent, Ca2+-induced Mitochondrial Dysfunction*. Journal of Biological Chemistry (2014).
3. Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models. Theranostics (2024).
4. Amyloid Beta and Phosphorylated Tau-Induced Defective Autophagy and Mitophagy in Alzheimer’s Disease. Cells (2019).