Mitochondrial microprotein MOCCI controls neuroinflammation by altering glial activation states.

Metabolic regulation and its underlying mechanisms play a critical role in controlling and resolving inflammation in the brain, directly shaping glial cell activation and the central nervous system's response to injury and disease. In our screen for microproteins that modify inflammatory outcomes, we discovered MOCCI (protein product of C15orf48/AA467197) as a significant regulator of gut and lung inflammation. However, its involvement in neuroinflammation is unknown. Here, we show that MOCCI is upregulated in microglia and astrocytes in both the mouse and human brain upon inflammation, and is required for orchestrating proper, complete, and beneficial activation of microglia and astrocytes. Induction of MOCCI triggers the transition of glia into a neuroprotective state and promotes the resolution of inflammation. In vitro, MOCCI deficiency leads to reduced migration, phagocytosis and cytokine secretion in microglia and astrocytes. In the cuprizone mouse model of multiple sclerosis, MOCCI plays a role in both demyelination and remyelination. These results position MOCCI as a molecular brake on neuroinflammation, highlighting its therapeutic potential for targeting glial metabolic health and resolving chronic CNS inflammation in neurodegenerative disease.