Identifying Mitochondrial Defects as a Common Denominator in Neurodegenerative Diseases: New Drug Targets Revealed by ER Junctions and Mitocytosis
Background
Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are key challenges threatening healthcare systems in an aging society. Existing drug development has focused on strategies to remove abnormal protein aggregates like amyloid-beta (Aβ) or alpha-synuclein (α-syn). However, since many protein aggregation inhibitors have failed to fundamentally halt the progression of cognitive decline or motor paralysis, there is a growing need to identify new pathological mechanisms.
Recently, the neurobiological community has focused on damage to mitochondria, the cellular powerhouses, as a common trigger for neuronal death. Neurons belong to the group of cells that consume the most glucose and oxygen in the human body. If ATP production through oxidative phosphorylation (OXPHOS), calcium homeostasis maintenance, reactive oxygen species (ROS) control, and apoptosis regulation fail, axonal transport and synaptic transmission are immediately paralyzed. While the affected areas and symptoms differ by individual disease, it is becoming increasingly clear that mitochondrial metabolic collapse is the turning point that accelerates neurodegeneration.
Key Findings
This study systematized mitochondrial dysfunction appearing in major neurodegenerative diseases by pathological type and presented previously overlooked new regulatory axes. In PD, aggregated α-syn directly damages electron transport chain Complex I, disturbs mitochondrial dynamics, and blocks the PINK1/Parkin-mediated mitophagy pathway. In AD, Aβ accumulation and hyperphosphorylated tau (p-Tau) proteins reduce respiratory complex activity and hinder organelle movement within axons, leading to the accumulation of damaged mitochondria. HD involves mutant huntingtin inducing complex membrane damage, and in multiple sclerosis (MS), reactive oxygen species generated by neuroinflammation trigger secondary dysfunction. Hereditary ALS mutations also cause electron transport chain assembly defects and imbalances in organelle fission and fusion.
Particularly noteworthy is the identification of three new molecular pathways beyond traditional respiratory complex defects. First is the mitocytosis pathway, where damaged mitochondria are packaged into migrasomes and expelled from the cell. Second is the error in electron transport chain protein synthesis due to mitochondrial aminoacyl-tRNA synthetase (mt-aaRS) dysfunction. Third is the disruption of the mitochondria-associated membrane (MAM), where the endoplasmic reticulum and mitochondria physically contact each other. When MAM contact sites are damaged, neurons experience a chain reaction of calcium overload and lipid transfer impairment. These complex defects trigger a vicious cycle of intracellular energy depletion, oxidative stress, and worsening protein aggregation, ultimately leading directly to neuronal death.
Significance and Outlook
This research, which revealed the common denominator of mitochondrial pathology, could serve as a turning point in shifting the focus of neurodegenerative disease treatment from protein removal to cellular metabolic reconstruction. It has laid the foundation to unify drug development strategies, which were previously fragmented by disease, into an integrated framework of organelle quality control. Approaches such as preserving Complex I activity with small molecules or structurally stabilizing MAM binding sites possess the potential for cross-application across multiple diseases beyond a single disorder.
However, significant barriers to clinical translation remain. The first challenge is securing blood-brain barrier (BBB) permeability and perfecting mitochondrial-targeted delivery technology. It is difficult to design formulations that precisely deliver drugs to damaged organelles in the central nervous system without affecting the metabolism of normal tissues. The lack of non-invasive biomarkers to measure the degree of mitochondrial damage in the early stages of disease is also cited as an obstacle in the patient selection process. Future research is expected to focus on verifying the in vivo safety of ER junction regulators and mitophagy activation factors.
Neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) place a substantial burden on global public health. Mounting evidence identifies mitochondrial dysfunction as a central contributor to neuronal damage and progressive brain functional decline. As a narrative review, this work aims to dissect mitochondrial‑associated pathological features across these major neurodegenerative disorders, summarize under‑recognized emerging mechanisms, and highlight translational bottlenecks for mitochondrial‑targeted therapies. Mitochondria sustain neuronal survival by mediating oxidative‑phosphorylation‑driven energy production, biomolecule biosynthesis, calcium homeostasis, reactive oxygen species (ROS) metabolism, and apoptotic regulation. In PD, aggregated α‑synuclein (α‑syn) damages respiratory‑chain complex I, perturbs mitochondrial dynamics and blocks PINK1/Parkin‑dependent mitophagy. In AD, amyloid‑β together with hyper‑phosphorylated tau (p-Tau) impairs respiratory complex activity, axonal mitochondrial trafficking and mitophagic clearance. Mutant huntingtin induces multiple mitochondrial lesions in HD, while inflammation‑triggered oxidative stress secondarily compromises mitochondrial function in MS. Pathogenic mutations in ALS disrupt respiratory‑chain assembly, mitochondrial dynamics and mitophagy. Beyond classic mitochondrial defects including respiratory‑chain impairment, dynamic imbalance and defective mitophagy, emerging mechanisms such as mitocytosis, mitochondrial aminoacyl‑tRNA synthetase (mt‑aaRS) dysfunction and mitochondria‑associated membrane (MAM) disruption are discussed. Mitochondrial dysfunction drives neurodegeneration via energy exhaustion, aggravated oxidative stress, pathological protein aggregation and excessive neuronal apoptosis. We further recapitulate mitochondrial‑oriented therapeutic approaches including small‑molecule regul
The results of this study can contribute to the diversification of neurodegenerative disease drug pipelines. The pharmaceutical industry is currently focusing on mitochondrial-targeted small molecule compounds as an alternative mechanism to overcome the low response rates and cerebral edema side effects of Aβ antibody therapies. Specifically, this applies directly to platform technologies that stabilize MAM interface proteins or the development of synthetic peptides that compensate for mitophagy deficiency. In the field of liquid biopsy-based diagnostics, scenarios such as using early screening tools by measuring mt-aaRS mutations or oxidatively damaged mitochondrial fragments within neuron-derived extracellular vesicles in patient blood could become a reality.