Sinsheimer, Andrew
(2019)
Understanding ACAD9 function and the physiologic consequences of its deficiency.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| 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 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37393 |
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