# Mitochondrial Dysfunction in the Inflammatory Process of Neurodegenerative Diseases

## TL;DR

This paper explores how mitochondrial dysfunction contributes to chronic inflammation in neurodegenerative diseases and identifies potential therapeutic strategies.

## Contribution

The paper highlights how respiratory supercomplex plasticity modulates ROS production and links mitochondrial injury to neuroinflammation.

## Key findings

- Impaired oxidative phosphorylation increases ROS and damages mitochondrial DNA.
- ROS promotes the release of mitochondrial damage-associated molecular patterns, activating inflammatory pathways.
- Therapeutic opportunities include supporting the electron transport chain and stabilizing supercomplexes.

## Abstract

Neurodegenerative diseases share a mitochondrial–immune axis in which impaired oxidative phosphorylation reshapes neuronal metabolism and drives chronic inflammation. Complex I play a redox gatekeeper role at the coenzyme Q (CoQ) junction: catalytic defects, misassembly, or reverse electron transport over-reduce the CoQ pool, increase electron leak, and elevate ROS. How respiratory supercomplex plasticity (CI-CIII2, CIII2-CIVn, or CI-CIII2-CIVn) modulates carrier channelling, flux control, and ROS propensity through dynamic reorganization of the electron transport chain is highlighted. Excess ROS damages lipids and mitochondrial DNA, promoting the release of mitochondrial damage-associated molecular patterns s that activate NLRP3 inflammasome signalling, cGAS-STING-dependent interferon programs, and endosomal TLR9 pathways, establishing feed-forward loops between mitochondrial injury and neuroinflammation. Disease-focused sections integrate evidence from Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis, and Huntington’s models, and map these mechanisms onto therapeutic opportunities spanning electron transport chain support, supercomplex stabilization, and consider mtDNA-sensing inflammatory nodes.