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Mitochondrial dysfunction and the metabolism - studies on respiratory chain disorders

Tomasic, Nikica LU (2021) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
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... (More)
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.
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author
supervisor
opponent
  • Associate professor Ćuk, Mario, Pediatric Endocrinology and Metabolic Medicine, Department of Pediatrics, School of Medicine, Zagreb, Croatia.
organization
publishing date
type
Thesis
publication status
published
subject
keywords
mitochondria, mitochondrial disease, metabolism, complex III, BCS1L
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2021:89
pages
62 pages
publisher
Lund University, Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/j/66942037055
defense date
2021-09-23 13:00:00
ISSN
1652-8220
ISBN
978-91-8021-096-6
language
English
LU publication?
yes
id
95d2d233-7e53-43b2-8f06-58dce4b495d6
date added to LUP
2021-09-01 10:57:22
date last changed
2021-09-13 14:13:07
@phdthesis{95d2d233-7e53-43b2-8f06-58dce4b495d6,
  abstract     = {{<b>Background:</b> Mutations of the mitochondrial assembly factor <i>BCS1L</i> disrupt assembly and function of the respiratory chain complex III (CIII) and thereby result in energy deprivation. In GRACILE syndrome, the <i>BCS1L</i> mutation causes a liver disorder that leads to metabolic disturbances associated with severe growth restriction.<br/><b>Objectives:</b> To clarify the mechanisms and affected metabolic pathways in the CIII deficiency disease progression and perform intervention trials in an experimental disease model. <br/><b>Methods/research questions:</b> A knock-in mouse model, carrying the same missense mutation (<i>Bcs1l</i> c.232A&gt;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 <i>BCS1L</i> 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.<br/>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.<br/><b>Results: </b>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 <i>BSC1L</i> 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. <br/><b>Significance:</b> 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. <br/>}},
  author       = {{Tomasic, Nikica}},
  isbn         = {{978-91-8021-096-6}},
  issn         = {{1652-8220}},
  keywords     = {{mitochondria, mitochondrial disease, metabolism, complex III, BCS1L}},
  language     = {{eng}},
  number       = {{2021:89}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Mitochondrial dysfunction and the metabolism - studies on respiratory chain disorders}},
  url          = {{https://lup.lub.lu.se/search/files/101902358/e_nailing_ex_Nikica.pdf}},
  year         = {{2021}},
}