Interventions to improve mitochondrial function in a mouse model of GRACILE syndrome : a complex III disorder

Research output: ThesisDoctoral ThesisCollection of Articles


A rare homozygous BCS1Lc.A232G (Ser78Gly, p.S78G) mutation in infants causes GRACILE syndrome, which is a severe mitochondrial respiratory chain complex III (CIII) disorder resulting in multiple organ dysfunction and early lethality. Pathogenesis mechanisms have been studied using our viable Bcs1lp.S78G knock-in mouse model. The mouse model replicates most clinical phenotypes, such as growth restriction, hepatopathy, and tubulopathy. Like patients, the survival of homozygous mice is reduced (to 35-45 days, P35-P45 in the C57BL/6JBomTac background), mainly because of severe hypoglycemia. Aiming to improve the glycemic balance we performed an intervention with a high sugar (60% dextrose) diet. This diet did not improve energy metabolism and resulted in slightly decreased survival despite apparent normalization of some plasma metabolites. For subsequent studies, we bred the Bcs1lc.A232G mutation into a C57BL/6JCrl background, in which the survival was five-fold longer (approximately 200 days). Moreover, the extended survival brought novel phenotypes, such as encephalopathy and late-onset cardiomyopathy. In this genetic background, we investigated the effect of ketogenic diet on disease progression. The ketogenic diet had a beneficial impact on liver disease, but it had adverse effects upon long-term feeding, resulting in shortened survival. In the third study, we introduced an alternative oxidase (AOX) transgene into the Bcs1lp.S78G mice to improve respiratory chain function. The ubiquitous expression of AOX, which should bypass electron transfer and relieve CIII blockade, prevented lethal cardiomyopathy and renal-tubular atrophy, and delayed focal astrogliosis in the somatosensory cortex of the brain. The beneficial effects of AOX extended the median survival of the homozygotes to median P590. The main conclusions from these studies are that the Bcs1lp.S78G mice in a C57BL/6JCrl background present with both the known early-onset manifestations of GRACILE syndrome and some later onset manifestations found in other CIII deficiencies. The dietary interventions had limited benefits, probably because of a severe course of the disease. In contrast, bypassing the blocked electron flow using AOX had a robust beneficial effect, mainly in tissues or cells with high ATP demand such as the heart and renal proximal tubular cells.
Original languageEnglish
  • Fellman, Vineta, Supervisor
  • Kallijärvi, Jukka, Supervisor
Place of PublicationHelsinki
Print ISBNs978-951-51-4947-3
Electronic ISBNs978-951-51-4948-0
Publication statusPublished - 2019
MoE publication typeG5 Doctoral dissertation (article)

Bibliographical note

M1 - 53 s. + liitteet

Fields of Science

  • Mitochondrial Diseases
  • Metabolism, Inborn Errors
  • Mice, Transgenic
  • Glucose
  • Blood Glucose
  • Diet, Ketogenic
  • Mitochondria
  • +genetics
  • +metabolism
  • Hypoglycemia
  • Acidosis, Lactic
  • Growth Disorders
  • Cardiomyopathies
  • Atrophy
  • Brain
  • Kidney
  • Liver
  • Disease Progression
  • Adenosine Triphosphate
  • NAD
  • Infant
  • Mortality, Premature
  • 3111 Biomedicine

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