Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation

Joshua S. Stoolman; Rogan A. Grant; Taylor A. Poor; Samuel E. Weinberg; Karis B. D’Alessandro; Jerica Tan; Jennifer Yuan Shih Hu; Megan E. Zerrer; Walter A. Wood; Madeline C. Harding; Sahil Soni; Karen M. Ridge; Paul T. Schumacker; G. R.Scott Budinger; Navdeep S. Chandel

doi:10.1038/s42255-024-01080-1

Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation

Joshua S. Stoolman^*, Rogan A. Grant, Taylor A. Poor, Samuel E. Weinberg, Karis B. D’Alessandro, Jerica Tan, Jennifer Yuan Shih Hu, Megan E. Zerrer, Walter A. Wood, Madeline C. Harding, Sahil Soni, Karen M. Ridge, Paul T. Schumacker, G. R.Scott Budinger, Navdeep S. Chandel^*

^*Corresponding author for this work

Research output: Contribution to journal › Letter › peer-review

2 Scopus citations

Abstract

Microglia are necessary for central nervous system (CNS) function during development and play roles in ageing, Alzheimer’s disease and the response to demyelinating injury^1–5. The mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation⁶ and macrophage-dependent immune responses^7–10. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Uqcrfs1 (Rieske iron-sulfur polypeptide 1) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation and adult CNS function in vivo. Notably, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA sequencing analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia. Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.

Original language	English (US)
Pages (from-to)	1492-1504
Number of pages	13
Journal	Nature Metabolism
Volume	6
Issue number	8
DOIs	https://doi.org/10.1038/s42255-024-01080-1
State	Published - Aug 2024

Funding

This work was supported by the National Institutes of Health (NIH) grants 2P01AG049665-06 to (N.S.C.), 2T32AI083216-11 to (J.S.S.) and 5T32HL076139-18 to (T.A.P.). Imaging work was performed at the Northwestern University Center for Advanced Microscopy supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Flow cytometric analysis was supported by the Northwestern University Flow Cytometry Core Facility supported by NCI CCSG P30 CA060553. Flow cytometry cell sorting was performed on a BD FACSAria SORP and the MACSQuant Tyto systems, purchased through the support of NIH grant 1S10OD011996-01. Metabolomics services were performed by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. MRI imaging was performed at the CTI Small Animal Imaging Core. The Morris water maize was performed at the Behavioural Phenotyping Core, while the rotarod, grip strength, open-field and Barnes maze tests were performed in the tissue and neurobehaviour phenotyping core as part of the NHLBI programme under grant no. 2P01AG049665-06. We thank H. Abdala-Valencia and the Pulmonary NextGen Sequencing Core for RNA sequencing.

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Physiology (medical)
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s42255-024-01080-1

Cite this

Stoolman, J. S., Grant, R. A., Poor, T. A., Weinberg, S. E., D’Alessandro, K. B., Tan, J., Hu, J. Y. S., Zerrer, M. E., Wood, W. A., Harding, M. C., Soni, S., Ridge, K. M., Schumacker, P. T., Budinger, G. R. S., & Chandel, N. S. (2024). Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation. Nature Metabolism, 6(8), 1492-1504. https://doi.org/10.1038/s42255-024-01080-1

@article{c10c522bb5bb4030a9b79f35f6bcee4f,

title = "Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation",

abstract = "Microglia are necessary for central nervous system (CNS) function during development and play roles in ageing, Alzheimer{\textquoteright}s disease and the response to demyelinating injury1–5. The mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses7–10. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Uqcrfs1 (Rieske iron-sulfur polypeptide 1) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation and adult CNS function in vivo. Notably, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA sequencing analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia. Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.",

author = "Stoolman, {Joshua S.} and Grant, {Rogan A.} and Poor, {Taylor A.} and Weinberg, {Samuel E.} and D{\textquoteright}Alessandro, {Karis B.} and Jerica Tan and Hu, {Jennifer Yuan Shih} and Zerrer, {Megan E.} and Wood, {Walter A.} and Harding, {Madeline C.} and Sahil Soni and Ridge, {Karen M.} and Schumacker, {Paul T.} and Budinger, {G. R.Scott} and Chandel, {Navdeep S.}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature Limited 2024.",

year = "2024",

month = aug,

doi = "10.1038/s42255-024-01080-1",

language = "English (US)",

volume = "6",

pages = "1492--1504",

journal = "Nature Metabolism",

issn = "2522-5812",

publisher = "Springer Berlin",

number = "8",

}

Stoolman, JS, Grant, RA, Poor, TA, Weinberg, SE, D’Alessandro, KB, Tan, J, Hu, JYS, Zerrer, ME, Wood, WA, Harding, MC, Soni, S, Ridge, KM , Schumacker, PT , Budinger, GRS & Chandel, NS 2024, 'Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation', Nature Metabolism, vol. 6, no. 8, pp. 1492-1504. https://doi.org/10.1038/s42255-024-01080-1

TY - JOUR

T1 - Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation

AU - Stoolman, Joshua S.

AU - Grant, Rogan A.

AU - Poor, Taylor A.

AU - Weinberg, Samuel E.

AU - D’Alessandro, Karis B.

AU - Tan, Jerica

AU - Hu, Jennifer Yuan Shih

AU - Zerrer, Megan E.

AU - Wood, Walter A.

AU - Harding, Madeline C.

AU - Soni, Sahil

AU - Ridge, Karen M.

AU - Schumacker, Paul T.

AU - Budinger, G. R.Scott

AU - Chandel, Navdeep S.

PY - 2024/8

Y1 - 2024/8

N2 - Microglia are necessary for central nervous system (CNS) function during development and play roles in ageing, Alzheimer’s disease and the response to demyelinating injury1–5. The mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses7–10. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Uqcrfs1 (Rieske iron-sulfur polypeptide 1) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation and adult CNS function in vivo. Notably, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA sequencing analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia. Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.

AB - Microglia are necessary for central nervous system (CNS) function during development and play roles in ageing, Alzheimer’s disease and the response to demyelinating injury1–5. The mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses7–10. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Uqcrfs1 (Rieske iron-sulfur polypeptide 1) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation and adult CNS function in vivo. Notably, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA sequencing analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia. Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.

UR - http://www.scopus.com/inward/record.url?scp=85199436657&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85199436657&partnerID=8YFLogxK

U2 - 10.1038/s42255-024-01080-1

DO - 10.1038/s42255-024-01080-1

M3 - Letter

C2 - 39048801

AN - SCOPUS:85199436657

SN - 2522-5812

VL - 6

SP - 1492

EP - 1504

JO - Nature Metabolism

JF - Nature Metabolism

IS - 8

ER -

Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this