Mitochondrial dysfunction and the metabolism - studies on respiratory chain disorders

Background: Mutations of the mitochondrial assembly factor BCS1L disrupt assembly and function of the respiratory chain complex III (CIII) and thereby result in energy deprivation. In GRACILE syndrome, the BCS1L mutation causes a liver disorder that leads to metabolic disturbances associated with severe growth restriction.
Objectives: To clarify the mechanisms and affected metabolic pathways in the CIII deficiency disease progression and perform intervention trials in an experimental disease model.
Methods/research questions: A knock-in mouse model, carrying the same missense mutation (Bcs1l c.232A>G) as the GRACILE syndrome patients, is used to study disease mechanisms and pathways involved. Two randomized controlled intervention studies have been performed on homozygous mice and littermate controls: a 4-hour fasting as a metabolic pressure to assess the compensatory capabilities, and a dietary intervention to clarify whether hypoglycemia and survival can be improved by the high-carbohydrate diet (60% dextrose). Further, phenotyping and the disease mechanism in a patient with a novel compound heterozygous BCS1L mutation have been studied and compared to GRACILE patients and mutant mice. In the last study, a metabolic phenotype caused by a single large-scale deletion (SLSD) in mitochondrial (mtDNA), including the genes for structural components of CI and CIII, was analyzed.
Methods used in the studies include genetic analysis,WES, WGS, phenotyping, blood and urine chemistry, metabolomics, histopathology, EM, function, and expression analysis. Conventional statistics and linear mixed-effect models (MEMs) were used for the analysis of the metabolic network response to fasting.
Results: Fasting mutant animals revealed intact systemic lipid mobilization but disrupted compensatory mechanisms leading to hypoglycemia. The high-carbohydrate diet had an unexpected adverse effect on survival compared to the standard diet. The novel BSC1L mutation had a different phenotype compared to GRACILE syndrome. The patient with the SLSD had a complex metabolic phenotype, which emphasized the importance of diagnostics synergy of clinical awareness, genetic and funtional analysis.
Significance: By elucidating metabolic disturbances, the project increases understanding of pathophysiology in CIII deficiency. This has a potential effect on understanding other, more common mitochondrial dysfunctions and raises new queries about this complex system.