Pan-cancer association of a mitochondrial function score with genomic alterations and clinical outcome

Mitochondria are pivotal in cellular energy metabolism and have garnered significant attention for their roles in cancer progression and therapy resistance. Despite this, the functional diversity of mitochondria across various cancer types remains inadequately characterized. This study seeks to fill this knowledge gap by introducing and validating MitoScore-a novel metric designed to quantitatively assess mitochondrial function across a wide array of cancers. Our investigation evaluates the capacity of MitoScore not only to distinguish between tumor and adjacent normal tissues but also to serve as a predictive marker for clinical outcomes. We analyzed gene expression data from 24 cancer types and corresponding normal tissues using the TCGA database. MitoScore was calculated by summing the normalized expression levels of six mitochondrial genes known to be consistently altered across multiple cancers. Differential gene expression was assessed using DESeq2, with a focus on identifying significant changes in mitochondrial function. MitoScore's associations with tumor proliferation, hypoxia, aneuploidy, and clinical outcomes were evaluated using Spearman's correlation, linear regression, and Kaplan-Meier survival analyses. MitoScore was significantly higher in tumor tissues compared to normal tissues across most cancer types (p < 0.001). It positively correlated with tumor proliferation rates (r = 0.46), hypoxia scores (r = 0.61), and aneuploidy (r = 0.44), indicating its potential as a marker of aggressive tumor behavior. High MitoScore was also associated with poorer prognosis in several cancer types, suggesting its utility as a predictive biomarker for clinical outcomes. This study introduces MitoScore, a metric for mitochondrial activity often elevated in tumors and linked to poor prognosis. It correlates positively with hypoxia and negatively with stromal and immune infiltration, highlighting mitochondria's role in the tumor microenvironment. MitoScore's association with genomic instability, such as aneuploidy, suggests mitochondrial dysfunction contributes to cancer progression. Despite challenges in mitochondrial-targeted therapies, MitoScore may identify tumors responsive to such treatments, warranting further research for clinical application.