The Human Mitochondrial Genome Encodes for an Interferon-Responsive Host Defense Peptide

Abstract

The mitochondrial DNA (mtDNA) can trigger immune responses and directly entrap pathogens, but it is not known to encode for active immune factors. The immune system is traditionally thought to be exclusively nuclear-encoded. Here, we report the identification of a mitochondrial-encoded host defense peptide (HDP) that presumably derives from the primordial proto-mitochondrial bacteria. We demonstrate that MOTS-c (mitochondrial open reading frame from the twelve S rRNA type-c) is a mitochondrial-encoded amphipathic and cationic peptide with direct antibacterial and immunomodulatory functions, consistent with the peptide chemistry and functions of known HDPs. MOTS-c targetedE. coliand methicillin-resistantS. aureus(MRSA), in part, by targeting their membranes using its hydrophobic and cationic domains. In monocytes, IFNγ, LPS, and differentiation signals each induced the expression of endogenous MOTS-c. Notably, MOTS-c translocated to the nucleus to regulate gene expression during monocyte differentiation and programmed them into macrophages with unique transcriptomic signatures related to antigen presentation and IFN signaling. MOTS-c-programmed macrophages exhibited enhanced bacterial clearance and shifted metabolism. Our findings support MOTS-c as a first-in-class mitochondrial-encoded HDP and indicates that our immune system is not only encoded by the nuclear genome, but also by the co-evolved mitochondrial genome.

Mitochondrial polymorphism m.3017C>T of SHLP6 relates to heterothermy

“…Administration of MOTS-c enhanced cold tolerance by boosting two mechanism that are needed for heterothermy, namely white fat browning and thermogenic gene expression in brown adipose tissue, a well-known organ for thermogenesis ( Lu et al, 2019 ). It downregulates circulating metabolites that are associated with type-2 diabetes and obesity, enhances glucose tolerance and insulin sensitivity ( Lee et al, 2015 ; Kim et al, 2018 ; Benayoun and Lee, 2019 ) and functions as a host-defence peptide according to a preprint ( Rice, 2023 ). Mitochondrial retrograde signalling, a major form of mitochondria to nucleus crosstalk that is activated by altered mitochondrial function under normal or pathophysiological conditions and enables reprogramming of nuclear gene expression ( Liu and Butow, 2006 ; Granat et al, 2020 ), is the likely route of MOTS-c-mediated metaboloprotection.…”