Mitochondrial complex I activity in microglia sustains neuroinflammation 2024 Peruzzotti-Jametti et al

Abstract

Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells2. 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. Ccomplex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system3.

Open access, https://www.nature.com/articles/s41586-024-07167-9

 

Some background references on reverse electron transport, also from Michael Murphy include —

How mitochondria produce reactive oxygen species (2009, Biochemical Journal)

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS (2014, Nature)

Control of mitochondrial superoxide production by reverse electron transport at complex I (2018, Journal of Biological Chemistry)

Preventing mitochondrial reverse electron transport as a strategy for cardioprotection (2023, Basic Research in Cardiology)

A break in mitochondrial endosymbiosis as a basis for inflammatory diseases (2024, Nature)

 

I wonder how peroxynitrite might be involved in this. Peroxynitrite scavengers made my ME symptoms much worse in a dose-dependent manner. IIRC, ONOO- is critical for inactivating IDO, which catabolizes TRP into kynurenines. Too complex for me to figure out right now.

 

This is a very common misconception - that somehow inflammation is 'perpetuated' by myeloid cell activity.

The inflammation in multiple sclerosis is due to an abnormal immune response, which causes trouble at the beginning, and does much the same from there on. Nothing 'perpetuates' the inflammation. It is continually being triggered by the same signals. The sensible approach to treatment is to get rid of those signals.