Mitochondrial complex I activity in microglia sustains neuroinflammation

L Peruzzotti-Jametti; C M Willis; G Krzak; R Hamel; L Pirvan; R-B Ionescu; J A Reisz; H A Prag; M E Garcia-Segura; V Wu; Y Xiang; B Barlas; A M Casey; A M R van den Bosch; A M Nicaise; L Roth; G R Bates; H Huang; P Prasad; A E Vincent; C Frezza; C Viscomi; G Balmus; Z Takats; J C Marioni; A D'Alessandro; M P Murphy; I Mohorianu; S Pluchino

doi:10.1038/s41586-024-07167-9

Mitochondrial complex I activity in microglia sustains neuroinflammation

L Peruzzotti-Jametti, C M Willis, G Krzak, R Hamel, L Pirvan, R-B Ionescu, J A Reisz, H A Prag, M E Garcia-Segura, V Wu, Y Xiang, B Barlas, A M Casey, A M R van den Bosch, A M Nicaise, L Roth, G R Bates, H Huang, P Prasad, A E VincentC Frezza, C Viscomi, G Balmus, Z Takats, J C Marioni, A D'Alessandro, M P Murphy, I Mohorianu, S Pluchino

Pharmacy

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

Abstract

Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis 1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells 2. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system 3.

Original language	English
Pages (from-to)	195-203
Number of pages	9
Journal	Nature
Volume	628
Issue number	8006
DOIs	https://doi.org/10.1038/s41586-024-07167-9
Publication status	Published - Apr 2024

Keywords

Animals
Female
Humans
Male
Mice
Central Nervous System/drug effects
Disease Models, Animal
Electron Transport/drug effects
Electron Transport Complex I/antagonists & inhibitors
Inflammation/drug therapy
Microglia/drug effects
Mitochondria/drug effects
Multiomics
Myeloid Cells/metabolism
Neuroinflammatory Diseases/drug therapy
Reactive Oxygen Species/metabolism

UN SDGs

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

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10.1038/s41586-024-07167-9

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Peruzzotti-Jametti, L., Willis, C. M., Krzak, G., Hamel, R., Pirvan, L., Ionescu, R.-B., Reisz, J. A., Prag, H. A., Garcia-Segura, M. E., Wu, V., Xiang, Y., Barlas, B., Casey, A. M., van den Bosch, A. M. R., Nicaise, A. M., Roth, L., Bates, G. R., Huang, H., Prasad, P., ... Pluchino, S. (2024). Mitochondrial complex I activity in microglia sustains neuroinflammation. Nature , 628(8006), 195-203. https://doi.org/10.1038/s41586-024-07167-9

@article{1dbcbe2a155344eca86d67d65c4c5264,

title = "Mitochondrial complex I activity in microglia sustains neuroinflammation",

abstract = "Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis 1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells 2. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system 3. ",

keywords = "Animals, Female, Humans, Male, Mice, Central Nervous System/drug effects, Disease Models, Animal, Electron Transport/drug effects, Electron Transport Complex I/antagonists & inhibitors, Inflammation/drug therapy, Microglia/drug effects, Mitochondria/drug effects, Multiomics, Myeloid Cells/metabolism, Neuroinflammatory Diseases/drug therapy, Reactive Oxygen Species/metabolism",

author = "L Peruzzotti-Jametti and Willis, {C M} and G Krzak and R Hamel and L Pirvan and R-B Ionescu and Reisz, {J A} and Prag, {H A} and Garcia-Segura, {M E} and V Wu and Y Xiang and B Barlas and Casey, {A M} and {van den Bosch}, {A M R} and Nicaise, {A M} and L Roth and Bates, {G R} and H Huang and P Prasad and Vincent, {A E} and C Frezza and C Viscomi and G Balmus and Z Takats and Marioni, {J C} and A D'Alessandro and Murphy, {M P} and I Mohorianu and S Pluchino",

note = "{\textcopyright} 2024. The Author(s).",

year = "2024",

month = apr,

doi = "10.1038/s41586-024-07167-9",

language = "English",

volume = "628",

pages = "195--203",

journal = "Nature ",

issn = "0028-0836",

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Peruzzotti-Jametti, L, Willis, CM, Krzak, G, Hamel, R, Pirvan, L, Ionescu, R-B, Reisz, JA, Prag, HA, Garcia-Segura, ME, Wu, V, Xiang, Y, Barlas, B, Casey, AM, van den Bosch, AMR, Nicaise, AM, Roth, L, Bates, GR, Huang, H, Prasad, P, Vincent, AE, Frezza, C, Viscomi, C, Balmus, G, Takats, Z, Marioni, JC, D'Alessandro, A, Murphy, MP, Mohorianu, I & Pluchino, S 2024, 'Mitochondrial complex I activity in microglia sustains neuroinflammation', Nature , vol. 628, no. 8006, pp. 195-203. https://doi.org/10.1038/s41586-024-07167-9

TY - JOUR

T1 - Mitochondrial complex I activity in microglia sustains neuroinflammation

AU - Peruzzotti-Jametti, L

AU - Willis, C M

AU - Krzak, G

AU - Hamel, R

AU - Pirvan, L

AU - Ionescu, R-B

AU - Reisz, J A

AU - Prag, H A

AU - Garcia-Segura, M E

AU - Wu, V

AU - Xiang, Y

AU - Barlas, B

AU - Casey, A M

AU - van den Bosch, A M R

AU - Nicaise, A M

AU - Roth, L

AU - Bates, G R

AU - Huang, H

AU - Prasad, P

AU - Vincent, A E

AU - Frezza, C

AU - Viscomi, C

AU - Balmus, G

AU - Takats, Z

AU - Marioni, J C

AU - D'Alessandro, A

AU - Murphy, M P

AU - Mohorianu, I

AU - Pluchino, S

PY - 2024/4

Y1 - 2024/4

N2 - Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis 1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells 2. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system 3.

AB - Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis 1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells 2. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system 3.

KW - Animals

KW - Female

KW - Humans

KW - Male

KW - Mice

KW - Central Nervous System/drug effects

KW - Disease Models, Animal

KW - Electron Transport/drug effects

KW - Electron Transport Complex I/antagonists & inhibitors

KW - Inflammation/drug therapy

KW - Microglia/drug effects

KW - Mitochondria/drug effects

KW - Multiomics

KW - Myeloid Cells/metabolism

KW - Neuroinflammatory Diseases/drug therapy

KW - Reactive Oxygen Species/metabolism

U2 - 10.1038/s41586-024-07167-9

DO - 10.1038/s41586-024-07167-9

M3 - Article

C2 - 38480879

SN - 0028-0836

VL - 628

SP - 195

EP - 203

JO - Nature

JF - Nature

IS - 8006

ER -

Mitochondrial complex I activity in microglia sustains neuroinflammation

Abstract

Keywords

UN SDGs

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