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Understanding ACAD9 function and the physiologic consequences of its deficiency

Sinsheimer, Andrew (2019) Understanding ACAD9 function and the physiologic consequences of its deficiency. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Acyl CoA Dehydrogenase 9 (ACAD9) is a member of the family of flavoenzymes that catalyze the dehydrogenation of Acyl-CoAs to 2,3 enoyl-CoAs in mitochondrial fatty acid oxidation (FAO). Inborn errors of metabolism of nearly all family members, including ACAD9, have been described in humans, and represent significant causes of morbidity and mortality particularly in children. ACAD9 deficiency leads to a combined defect in fatty acid oxidation and oxidative phosphorylation (OXPHOS) due to a duel role in the pathways. In addition to its function in mitochondrial FAO, ACAD9 has been shown to have a second function as one of 14 factors responsible for assembly of complex I of the electron transport chain (ETC). Considerable controversy remains over the relative role of these two functions in normal physiology and the disparate clinical findings described in patients with ACAD9 deficiency.
In response to previous non-viable attempts at creating a mouse null for ACAD9 activity, several models were developed using Cre-lox to tailor knockout of the gene in specific tissues as well as allow induction of knockout in all tissues during adulthood. These models proved to have functional and biochemical phenotypes comparable to the affected tissue in humans and allowed testing of several novel therapies to assess their potential for use in humans with ACAD9 deficiency.
Tissues from these animals were also used to examine a second complex I assembly factor, Evolutionarily Conserved Signaling Intermediate in Toll pathway (ECSIT), and its interaction with ACAD9. ECSIT levels were significantly reduced in the absence of ACAD9.
These data help elucidate the physiological impact of ACAD9 deficiency, as well as provide new options for therapy of this otherwise untreatable disease. ACAD9 is the most common cause of isolated complex I deficiency in humans, underscoring the public health significance of these studies have relative to diagnosis and treatment.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Sinsheimer, Andrewans204@pitt.eduans204
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVockely,
Committee MemberKammerer, Candacecmk3@pitt.educmk3
Committee MemberGoetzman,
Committee MemberFinegold, Daviddnf@pitt.edudnf
Date: 26 September 2019
Date Type: Publication
Defense Date: 23 April 2019
Approval Date: 26 September 2019
Submission Date: 19 August 2019
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 107
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: ACAD9 – Acyl-CoA dehydrogenase family member 9 BNGE – Blue native gel electrophoresis CBP – Cardiolipin-binding Peptide (Bendavia-like) DMSO – Dimethyl sulfoxide ETC – Electron transport chain FAO – Fatty acid oxidation FAOD – Fatty acid oxidation disorders FBS – Fetal bovine serum H&E – Haemotoxylin and Eosin HWT – Hanging Wire Test IF – Immunofluorescence IHC – Immunohistochemistry PBS – Phosphate buffered saline PBST – Phosphate buffered saline with Tween 20 ROS – Reactive oxygen species SDS-PAGE – Sodium dodecyl sulfate polyacrylamide gel electrophoresis WB – Western blot
Date Deposited: 26 Sep 2019 16:36
Last Modified: 26 Sep 2019 16:36


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