Faculty Collaboration Database

Optical Metabolic Imaging of Mitochondrial Dysfunction on HADH Mutant Newborn Rat Hearts. IEEE J Transl Eng Health Med 2021;9:1800407

Date

09/01/2021

Pubmed ID

34462673

Pubmed Central ID

PMC8396955

DOI

10.1109/JTEHM.2021.3104966

Scopus ID

2-s2.0-85113252876 (requires institutional sign-in at Scopus site)   6 Citations

Abstract

BACKGROUND: Mitochondrial [Formula: see text]-oxidation of fatty acids is the primary energy source for the heart and carried out by Hydroxy Acyl-CoA Dehydrogenase (HADH) encoded trifunctional protein. Mutations in the genes encoding mitochondrial proteins result in functionally defective protein complexes that contribute to energy deficiencies, excessive reactive oxygen species (ROS) production, and accumulation of damaged mitochondria. We hypothesize that a dramatic alternation in redox state and associated mitochondrial dysfunction is the underlying cause of Fatty Acid Oxidation (FAO) deficiency mutant, resulting in heart failure. Mitochondrial co-enzymes, NADH and FAD, are autofluorescent metabolic indices of cells when imaged, yield a quantitative assessment of the cells' redox status and, in turn, that of the tissue and organ.

METHOD: We utilized an optical cryo-imager to quantitively evaluate the three-dimensional distribution of mitochondrial redox state in newborn rats' hearts and kidneys. Redox ratio (RR) assessment shows that mitochondrial dysfunction is extreme and could contribute to severe heart problems and eventual heart failure in the mutants.

RESULTS: Three-dimensional redox ratio (NADH/FAD) rendering, and the volumetric mean value calculations confirmed significantly decreased cardiac RR in mutants by 31.90% and 12.32%, in renal mitochondrial RR compared to wild-type control. Further, histological assessment of newborn heart myocardial tissue indicated no significant difference in myocardial tissue architecture in both control and severe (HADHA^e4-/-) conditions.

CONCLUSION: These results demonstrate that optical imaging can accurately estimate the redox state changes in newborn rat organs. It is also apparent that the FAO mutant's heart tissue with a low redox ratio is probably more vulnerable to cumulative damages than kidneys and fails prematurely, contributing to sudden death.

Author List

Foomani FH, Jarzembowski JA, Mostaghimi S, Mehrvar S, Kumar SN, Ranji M

Authors

Jason A. Jarzembowski MD, PhD Sr Associate Dean, CEO CSG, Professor in the Pathology department at Medical College of Wisconsin
Suresh Kumar PhD Associate Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acyl-CoA Dehydrogenase
Animals
Animals, Newborn
Mitochondria
Myocardium
Oxidation-Reduction
Rats