Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology

Area of Science:

• Neuroscience
• Cellular Biology
• Biochemistry

Background:

• Neurodegenerative diseases disrupt mitochondrial function, including reactive oxygen species (ROS) production.
• Mitochondrial complex III (CIII) is a known ROS generator, but its specific role in neurodegeneration is unclear.

Purpose of the Study:

• To investigate CIII as a primary ROS source in astrocytes under neuropathology-related stress.
• To elucidate the mechanisms and consequences of CIII-derived ROS in neurological disease.

Main Methods:

• Utilized site-selective suppressors and genetic manipulations.
• Employed live mitochondrial ROS imaging and multiomic profiling.
• Investigated CIII ROS dependence on nuclear factor-κB (NF-κB) and mitochondrial sodium-calcium exchanger (NCLX).

Main Results:

• CIII was identified as a dominant ROS producer in stressed astrocytes.
• Astrocytic CIII ROS production is regulated by NF-κB and NCLX.
• CIII ROS mediate protein oxidation, amplify astrocytic metabolic and transcriptional changes (STAT3-dependent), and induce neuronal toxicity.
• Therapeutic CIII ROS suppression in mice reduced tauopathy, neuroinflammation, and extended lifespan.

Conclusions:

• CIII-derived ROS act as critical immunometabolic signals in neurodegeneration.
• Targeting CIII ROS presents a viable therapeutic avenue for neurodegenerative disorders.