Dataset Information

Mitoproteomics of neuronal mitochondria of EAE mice

ABSTRACT: Inflammation in the central nervous system (CNS) can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). Here we combine cell type-specific mitochondrial proteomics with in vivo biosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. Neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP depletion, which precedes mitochondrial oxidation and calcium overload. This early axonal energy crisis is associated with impaired electron transport chain function, but also an upstream dysbalance of tricarboxylic acid (TCA) cycle enzymes. Isocitrate dehydrogenase 3 (Idh3), the rate limiting enzyme of the TCA cycle, is depleted in neuronal mitochondria in experimental models and in human MS lesions. Notably, viral overexpression of Idh3 can rectify the axonal energy deficits, suggesting that TCA cycle dysfunction in neuroinflammation may be amendable to therapy.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Neuron

DISEASE(S): Multiple Sclerosis

SUBMITTER: Stephan Mueller

LAB HEAD: Stefan F. Lichtenthaler

PROVIDER: PXD032363 | Pride | 2023-10-18

REPOSITORIES: Pride

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Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions.

Tai Yi-Heng YH Engels Daniel D Locatelli Giuseppe G Emmanouilidis Ioanna I Fecher Caroline C Theodorou Delphine D Müller Stephan A SA Licht-Mayer Simon S Kreutzfeldt Mario M Wagner Ingrid I de Mello Natalia Prudente NP Gkotzamani Sofia-Natsouko SN Trovò Laura L Kendirli Arek A Aljović Almir A Breckwoldt Michael O MO Naumann Ronald R Bareyre Florence M FM Perocchi Fabiana F Mahad Don D Merkler Doron D Lichtenthaler Stefan F SF Kerschensteiner Martin M Misgeld Thomas T

Nature metabolism 20230710 8

Inflammation in the central nervous system can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). Here we combine cell-type-specific mitochondrial proteomics with in vivo biosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. We show that neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal A ...[more]

PMID: 37430025

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Project description:Spinocerebellar ataxia type 3 (SCA3/MJD) has a polyQ etiology but, the current knowledge on molecular processes and proteins involved in pathogenesis is insufficient. Due to its proteolytic function, Ataxin-3 can influence other proteins, yet the global picture of crucial proteins and pathways in SCA3 was not investigated previously. Here, we explored molecular SCA3 mechanism by interdisciplinary research paradigm combining SCA3 knock-in model, behavior, MRI, brain proteomics, precise axonal proteomics, neuronal energy recordings, labeling of vesicles, and inclusions and focusing in axonal compartment. Using the global proteomics, we found dysregulation of protein homeostasis over the entire disease progression. The early SCA3 phase was associated with reduced body weight gain, the presence of the number of dysregulated proteins related to metabolism and mitochondria, and an altered profile of oxygen consumption rate in neurons. Moreover, the early phase presented alterations of protein metabolism, cytoskeletal architecture, axonal and synaptic proteins. Protein dysregulations indicated that the compartment involved in SCA3 pathogenesis next to the mitochondria are also neuronal processes and axons in particular. To confirm that the axon is one of the central compartments in SCA3 pathogenesis, we performed targeted proteomics on axons and somatodendritic compartments. We revealed highly increased axonal localization of protein synthesis machinery, including ribosomes, translation factors, and RNA binding proteins, while the level of proteins responsible for cellular transport and mitochondria was decreased. In summary, the SCA3 disease mechanism is based on the broad influence of mutant ataxin-3 on the neuronal proteome. Processes central in our SCA3 model include disturbed localization of proteins between axonal and somatodendritic compartment, early neuronal energy deficit, altered neuronal cytoskeletal structure, an overabundance of protein synthetic machinery in axons.

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	aEAE_raw.zip	Other
	aEAE_txt.zip	Other
	cEAE_raw.zip	Other
	cEAE_txt.zip	Other
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