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Mitochondrial folate one-carbon metabolism moderates Alzheimer’s disease pathology

ABSTRACT: Familial forms of AD cause a loss of neurons associated with the accumulation of toxic amyloid β peptide (Aβ) and mitochondrial dysfunction. We found that flies over expressing a toxic form of Aβ (Aβ-Arc) exhibit altered components of mitochondrial complex I and one-carbon (1C) metabolism.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Drosophila Melanogaster (fruit Fly)

TISSUE(S): Whole Body

SUBMITTER: Luis Martins

LAB HEAD: L. Miguel Martins

PROVIDER: PXD040263 | Pride | 2025-05-06

REPOSITORIES: Pride

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			Action	DRS
	Experiment_3.msf	Msf
	Experiment_3_F1.raw	Raw
	Experiment_3_F10.raw	Raw
	Experiment_3_F11.raw	Raw
	Experiment_3_F12.raw	Raw

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Publications

Enhancing mitochondrial one-carbon metabolism is neuroprotective in Alzheimer's disease models.

Yu Yizhou Y Chen Civia Z CZ Celardo Ivana I Tan Bryan Wei Zhi BWZ Hurcomb James D JD Leal Nuno Santos NS Popovic Rebeka R Loh Samantha H Y SHY Martins L Miguel LM

Cell death & disease 20241124 11

Alzheimer's disease (AD) is the most common form of age-related dementia. In AD, the death of neurons in the central nervous system is associated with the accumulation of toxic amyloid β peptide (Aβ) and mitochondrial dysfunction. Mitochondria are signal transducers of metabolic and biochemical information, and their impairment can compromise cellular function. Mitochondria compartmentalise several pathways, including folate-dependent one-carbon (1C) metabolism and electron transport by respirat ...[more]

PMID: 39582067

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Mitochondrial RNA in Alzheimer’s Disease Circulating Extracellular Vesicles

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Expression data from Saccharomyces cerevisiae

Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Oligomers of Amyloid-β peptides (Aβ) are thought to play a pivotal role in AD pathogenesis, yet the mechanisms involved remain unclear. Two major isoforms of Aβ associated with AD are Aβ40 and Aβ42, the latter being more prone to form oligomers and toxic. Humanized yeast models are currently applied to unravel the cellular mechanisms behind Aβ toxicity. Here, we took a systems biology approach to study two yeast AD models which expressed either Aβ40 or Aβ42 in bioreactor cultures. Strict control of oxygen availability and culture pH, strongly affected the chronological lifespan and reduced confounding effects of variations during cell growth. Reduced growth rates and biomass yields were observed upon expression of Aβ42, indicating a redirection of energy from growth to maintenance. Quantitative physiology analyses furthermore revealed reduced mitochondrial functionality and ATP generation in Aβ42 expressing cells, which matched with observed aberrant fragmented mitochondrial structures. Genome-wide expression levels analysis showed that Aβ42 expression triggers strong ER stress and unfolded protein responses (UPR). Expression of Aβ40 induced only mild ER stress, leading to activation of UPR target genes that cope with misfolded proteins, which resulted in hardly affected physiology. The combination of well-controlled cultures and AD yeast models strengthen our understanding of how cells translate different levels of Aβ toxicity signals into particular cell fate programs, and further enhance their role as a discovery platform to identify potential therapies.

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