Nat Commun. 2021 Apr 09. 12(1): 2130
Cheryl Q E Lee,
Baptiste Kerouanton,
Sonia Chothani,
Shan Zhang,
Ying Chen,
Chinmay Kumar Mantri,
Daniella Helena Hock,
Radiance Lim,
Rhea Nadkarni,
Vinh Thang Huynh,
Daryl Lim,
Wei Leong Chew,
Franklin L Zhong,
David Arthur Stroud,
Sebastian Schafer,
Vinay Tergaonkar,
Ashley L St John,
Owen J L Rackham,
Lena Ho.
Mito-SEPs are small open reading frame-encoded peptides that localize to the mitochondria to regulate metabolism. Motivated by an intriguing negative association between mito-SEPs and inflammation, here we screen for mito-SEPs that modify inflammatory outcomes and report a mito-SEP named "Modulator of cytochrome C oxidase during Inflammation" (MOCCI) that is upregulated during inflammation and infection to promote host-protective resolution. MOCCI, a paralog of the NDUFA4 subunit of cytochrome C oxidase (Complex IV), replaces NDUFA4 in Complex IV during inflammation to lower mitochondrial membrane potential and reduce ROS production, leading to cyto-protection and dampened immune response. The MOCCI transcript also generates miR-147b, which targets the NDUFA4 mRNA with similar immune dampening effects as MOCCI, but simultaneously enhances RIG-I/MDA-5-mediated viral immunity. Our work uncovers a dual-component pleiotropic regulation of host inflammation and immunity by MOCCI (C15ORF48) for safeguarding the host during infection and inflammation.