Mechanistic description
Age-dependent oxidation and deamidation of synaptic mitochondrial proteins (including VDAC1, CypD/PPID, and MICOS complex members) impairs calcium handling and ATP generation, creating a chronic energy deficit that uncouples synaptic vesicle release probability from activity demands and triggers compensatory synaptic loss.
Mechanism / pathway
- PPID (Cyclophilin D)
- neurodegeneration
Evidence for (5)
ATP in Mitochondria: Quantitative Measurement, Regulation, and Physiological Role.
Morphology and ATP-ase of isolated mitochondria.
Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.
In situ structure and rotary states of mitochondrial ATP synthase in whole Polytomella cells.
Localized glucose import, glycolytic processing, and mitochondria generate a focused ATP burst to power basement-membrane invasion.
Evidence against (2)
Advantages and limitations of the equine disease, pituitary pars intermedia dysfunction as a model of spontaneous dopaminergic neurodegenerative disease.
Equine pituitary pars intermedia dysfunction: current perspectives on diagnosis and management.
Evidence matrix
Supporting
- ATP in Mitochondria: Quantitative Measurement, Regulation, and Physiological Role. PMID:41453923 · 2025 · Biochemistry (Mosc)
- Morphology and ATP-ase of isolated mitochondria. PMID:14381435 · 1955 · J Biophys Biochem Cytol
- Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy. PMID:40203117 · 2025 · Sci Adv
- In situ structure and rotary states of mitochondrial ATP synthase in whole Polytomella cells. PMID:39236170 · 2024 · Science
- Localized glucose import, glycolytic processing, and mitochondria generate a focused ATP burst to power basement-membrane invasion. PMID:35316617 · 2022 · Dev Cell
Contradicting
- Advantages and limitations of the equine disease, pituitary pars intermedia dysfunction as a model of spontaneous dopaminergic neurodegenerative disease. PMID:17374512 · 2007 · Ageing Res Rev
- Equine pituitary pars intermedia dysfunction: current perspectives on diagnosis and management. PMID:30101114 · 2015 · Vet Med (Auckl)
Cite this hypothesis
Cite this hypothesis
etl-backfill (2026). Synaptic Mitochondrial Proteostasis Collapse Disrupts ATP-Demand Coupling at Ac…. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/hyp-SDA-2026-04-04-frontier-proteomics-1c3dba72-2
@misc{scidex_hypothesis_hypsda20,
title = {Synaptic Mitochondrial Proteostasis Collapse Disrupts ATP-Demand Coupling at Ac…},
author = {etl-backfill},
year = {2026},
howpublished = {SciDEX hypothesis},
url = {https://prism.scidex.ai/hypotheses/hyp-SDA-2026-04-04-frontier-proteomics-1c3dba72-2},
note = {SciDEX artifact hypothesis:hyp-SDA-2026-04-04-frontier-proteomics-1c3dba72-2}
}