Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration
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Abstract
Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders.
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During axon degeneration, NMNAT2 axonal transport is blocked, and the axonal pool of the protein is rapidly degraded, leading to critical depletion of NAD+ in the axon.
“during axon degeneration, NMNAT2 axonal transport is blocked, and the axonal pool of the protein is rapidly degraded, leading to a critical depletion of NAD+ in the axon142,143.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [143]
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- Authors
- Loreto, A., Hill, C. S., Hewitt, V. L., Orsomando, G., Angeletti, C., Gilley, J., Lucci, C., Sanchez-Martinez, A., Whitworth, A. J., Conforti, L., Dajas-Bailador, F., & Coleman, M. P.
- Affiliations
- University of Cambridge (GB)
- Marche Polytechnic University (IT)
- University of Nottingham (GB)
- Corresponding author
- Loreto, Andrea
- Coleman, Michael P.
- ORCID
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 134
- Pages
- 104678
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC7611775
- OpenAlex
- W2984519822
- Cited by
- 131
- References
- 51
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 23 · 2023: 16 · 2022: 22 · 2021: 30 · 2020: 13 · 2019: 1
- FWCI
- 7.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, other-oa)
- PubMed Central (acceptedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion, cc-by-nc-nd)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Medical Research Council
- Parkinson's UK
- Wellcome Trust
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- Wallerian degeneration, mitochondrial dysfunction, NMNAT2, SARM1, axonal degeneration, mitochondrial membrane potential, mitochondrial uncoupling, axonal transport, sympathetic neurons, NAD biosynthesis, PINK1, mitochondrial disease, neuroprotection
- MeSH terms
- Animals, Axons, Cytoskeletal Proteins, Drosophila, Male, Mice, Inbred C57BL, Mitochondria, Nicotinamide-Nucleotide Adenylyltransferase, Wallerian Degeneration, Armadillo Domain Proteins, Membrane Potential, Mitochondrial
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