Plasma mitochondrial-associated proteins scale with illness severity and predict outcome in suspected sepsis

Abstract

Mitochondrial dysfunction has been implicated in sepsis-related organ failure. We investigated whether plasma profiles of mitochondrial-associated proteins are associated with illness severity and short-term outcomes and explored whether they reveal distinct mitochondrial subphenotypes. In this post hoc analysis of the Acutelines data-biobank, we included 213 adult patients presenting to the emergency department with a suspicion of sepsis, with infection confirmed by independent adjudication. Blood plasma proteins of patients were quantified with the Olink Explore HT platform; of 5,416 proteins, 232 mitochondrial-associated proteins (MitoCarta3.0) were z-standardized and averaged per patient to derive a continuous mitochondrial-protein score. To explore whether operationally distinct patient groups could be identified along this gradient, we additionally performed principal component analysis with K-means clustering on the same protein set. Differential abundance analysis, pathway enrichment, and least absolute shrinkage and selection operator regression were performed as exploratory analyses. The continuous mitochondrial-associated protein score increased with illness severity (Spearman ρ 0.18–0.29; p < 0.01) and worse 72-hour outcomes (odds ratio per standard deviation: organ failure-free survival 0.57; intensive care unit admission 1.66; mortality 2.36). Exploratory clustering identified two groups differing mainly in overall mitochondrial-associated protein abundance. Considerable overlap and limited support for a discrete two-cluster structure suggested variation along a continuum rather than clearly distinct mitochondrial subphenotypes. Exploratory pathway analyses implicated mitochondrial metabolism, cellular stress, and injury-related processes. Higher plasma mitochondrial-associated protein abundance was associated with greater illness severity and worse short-term outcomes in suspected sepsis. These associations are hypothesis-generating, providing a first step toward understanding the role of mitochondrial dysfunction in sepsis severity.