Immune Cell Mitochondrial Phenotypes Are Largely Preserved in Mitochondrial Diseases and Do Not Reflect Disease...

The aim of this study was to profile immune cell mitochondrial phenotypes in mitochondrial diseases (MitoD) and evaluate how these phenotypes relate to disease manifestations or biomarkers.

We profiled mitochondrial content and oxidative phosphorylation (OxPhos) enzymatic activities in isolated monocytes, lymphocytes, neutrophils, platelets, and mixed peripheral blood mononuclear cells (PBMCs) from 37 individuals with MitoD (m.3243A > G, n = 23; single, large-scale mitochondrial DNA (mtDNA) deletions, n = 14) and 68 healthy women and men from the Mitochondrial Stress, Brain Imaging, and Epigenetics study.

We first confirmed and quantified robust cell type differences in mitochondrial content; activities of OxPhos complexes I, II, and IV; and the mitochondrial respiratory capacity (MRC) index. In relation to MitoD, neither mitochondrial content nor OxPhos capacity was consistently affected, other than a mild monocyte-specific reduction in complex I (partially mtDNA encoded) relative to complex II (entirely nDNA encoded), consistent with the mtDNA defects examined. Relative to the large differences in cell type-specific mitochondrial phenotypes, differences in MitoD relative to controls were generally small (<25%) across mitochondrial measures. MitoD biomarkers growth differentiation factor 15 and fibroblast growth factor 21, as well as clinical disease severity measures, were most strongly related to mitochondrial abnormalities in platelets, and most weakly related to mitochondrial OxPhos capacity in lymphocytes, which are known to eliminate mtDNA defects. Finally, comparing PBMCs collected in the morning/fasted state with those in the afternoon/fed state after a stressful experience, we report significant time-dependent changes in mitochondrial biology over hours.

Overall, these results demonstrate that the dynamic and cell type-specific mitochondrial phenotypes are preserved in MitoD and are generally unrelated to symptom severity.