Mitochondrial perturbation adapts the proteome from early to advanced immune responses
Dysregulated immunity, a hallmark of many human diseases, co-occurs with mitochondrial dysfunction and is commonly associated with misprimed primary immune signaling. While transcriptionally well-characterized, the impact of mitochondria on the host response at the protein level is less clear. Using in vitro and in vivo approaches including proteotranscriptomics, our data suggest that OXPHOS…
Mitochondrial dysfunction, often linked to various human diseases, is frequently accompanied by impaired immune signaling. Traditionally, researchers have focused on the transcriptional aspects of this relationship, but the protein-level effects of mitochondria on host responses remain poorly understood. To investigate this, the study employed in vitro and in vivo methodologies, including proteotranscriptomics, to examine the role of mitochondrial function in immune protein expression.
The findings reveal that mitochondrial oxidative phosphorylation (OXPHOS) stimulates the production of early immune proteins that operate within individual cells. Conversely, mitochondrial perturbation triggers mediators responsible for cell extrinsic responses, such as inflammation. Importantly, this effect is not influenced by additional immune signals and occurs in a time-dependent manner that is highly conserved across various tissues in mouse models exhibiting mitochondrial dysfunction.
These results highlight previously unrecognized roles for mitochondrial state in modulating the host's protein-level response to immune challenges, offering insights into the underlying mechanisms of complex diseases. Furthermore, the findings suggest a potential evolutionary link between mitochondrial dysfunction and the development of eukaryotic immune sensing systems.
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