Journal article
Mitochondrial Complex I and ROS control neuromuscular function through opposing pre- and postsynaptic mechanisms
PLoS biology, Vol.23(9), e3003388
09/22/2025
DOI: 10.1371/journal.pbio.3003388
PMCID: PMC12478897
PMID: 40982549
Abstract
Neurons require high amounts of energy, and mitochondria help to fulfill this requirement. Dysfunctional mitochondria trigger problems in various neuronal tasks. Using the Drosophila neuromuscular junction (NMJ) as a model synapse, we previously reported that Mitochondrial Complex I (MCI) subunits were required for maintaining NMJ function and growth. Here, we report tissue-specific adaptations at the NMJ when MCI is depleted. In Drosophila motor neurons, MCI depletion causes profound cytological defects and increased mitochondrial reactive oxygen species (ROS). But instead of diminishing synapse function, neuronal ROS triggers a homeostatic signaling process that maintains normal NMJ excitation. We identify molecules mediating this compensatory response. MCI depletion in muscles also enhances local ROS. But high levels of muscle ROS cause destructive responses: synapse degeneration, mitochondrial fragmentation, and impaired neurotransmission. In humans, mutations affecting MCI subunits cause severe neurological and neuromuscular diseases. The tissue-level effects that we describe in the Drosophila system are potentially relevant to forms of mitochondrial pathogenesis.
Details
- Title: Subtitle
- Mitochondrial Complex I and ROS control neuromuscular function through opposing pre- and postsynaptic mechanisms
- Creators
- Bhagaban Mallik - University of IowaSajad A. Bhat - Stanford UniversityXinnan Wang - Stanford UniversityC. Andrew Frank - University of Iowa
- Resource Type
- Journal article
- Publication Details
- PLoS biology, Vol.23(9), e3003388
- DOI
- 10.1371/journal.pbio.3003388
- PMID
- 40982549
- PMCID
- PMC12478897
- NLM abbreviation
- PLoS Biol
- ISSN
- 1545-7885
- eISSN
- 1545-7885
- Publisher
- PUBLIC LIBRARY SCIENCE
- Grant note
- NIH/NINDS: NS085164, NS130108, NS136753, NS128040 University of Iowa's Carver College of Medicine
B.M. was supported in part by NIH/NINDS (https://www.ninds.nih.gov) grants to C.A.F. (NS085164, NS130108, and NS136753). Collectively, the work was supported by those same NIH/NINDS grants, as well as funds from the University of Iowa's Carver College of Medicine (https://medicine.uiowa. edu) to C.A.F. Funding supporting the work executed by S.A.B. and X.W. was from an NIH/NINDS (https://www.ninds.nih.gov) R01 grant NS128040 to X.W. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- Language
- English
- Date published
- 09/22/2025
- Academic Unit
- Anatomy and Cell Biology; Iowa Neuroscience Institute; Biology
- Record Identifier
- 9984966333502771
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