WHOLE MITOGENOME SEQUENCING UNCOVERS A RELATION BETWEEN MITOCHONDRIAL HETEROPLASMY, OXIDATIVE PHOSPHORYLATION AND LEPROSY SEVERITY
In recent years, an intimate mitochondria/immune system interaction has been proposed, so that variants in the mitochondrial genome might deregulate important metabolic processes in the combat of infections, such as leprosy, mainly caused by Mycobacterium leprae. It should also be noted that heteroplasmy, the coexistence of different mtDNA copies, might be involved in the deregulation of cell functions essential for homeostasis, including immune processes. However, these relations have been widely overlooked. Here, we sequenced the whole mitochondrial genome to investigate variants and their heteroplasmy levels, considering patients with different clinical forms of leprosy and household contacts. Results: We found 140 variants in at least two of the subtypes of the case group (Borderline Tuberculoid, Borderline Lepromatous, Lepromatous), suggesting a possible clinical significance to these variants. Notably, 16 variants were exclusively found in the three clinical forms, including m.3791T>C in MT-ND1, m.5317C>A in MT-ND2, m.8545G>A in MT-ATP8, m.9044T>C in MT-ATP6 and m.15837T>C in MT-CYB. Importantly, our results also suggest a strong association between levels of heteroplasmy and leprosy, more specifically in protein-coding, regulatory and rRNA regions possibly impacting the energy generation process. It seems that heteroplasmy across the mitochondrial genome can occur differently in each region depending on the affected or unaffected state and the clinical form that leprosy presents, Conclusions: We found a significant number of mitochondrial variants and more diverse heteroplasmy levels in the leprosy patients from our cohort, suggesting for the first time that the mitochondrial genome, and particularly heteroplasmy, might be involved with the leprosy process and the distinction of clinical forms, through oxidative phosphorylation instability and dysregulation in this infection.