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Investigating the Hypersuccinylation of Respiratory Complexes in Defective SUCLA2 Disease

Author: Tuomas Kukkonen
Supervisor: Juho Rousu

Abstract: The defective SUCLA2 disease is a pediatric mitochondrial disease that impairs both muscular and neurological function. Although the primary pathogenic mechanism remains unclear, a pronounced hypersuccinylation phenotype has been identified in patient-derived cells. In particular, components of the electron transport chain (ETC) exhibit extensive hypersuccinylation. ETC dysfunction is also a common feature of the disease. Previous metabolomic analyses further implicate this pathway in disease pathology.

This thesis investigates whether hypersuccinylation could contribute to altered ETC activity with a combination of in silico structural modelling, evolutionary conservation analysis of target lysines, and permutation-based statistical approaches.

The results suggest multiple plausible mechanisms by which hypersuccinylation could modulate ETC in SUCLA2 disease. These include disruption of substrate binding in respiratory complex I, modulation of an allosteric regulatory site in complex IV, and alteration of cyclophilin D binding affinity to complex V. The mechanisms presented in this thesis have not been reported previously. Collectively, these findings generate testable hypotheses for disease pathogenesis and provide new insights into the functional consequences of protein succinylation.