ORCID Profile
0000-0003-3784-4816
Current Organisation
The University of Auckland
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Publisher: The Royal Society
Date: 03-10-2022
Abstract: Diabetic cardiomyopathy is a leading cause of heart failure in diabetes. At the cellular level, diabetic cardiomyopathy leads to altered mitochondrial energy metabolism and cardiomyocyte ultrastructure. We combined electron microscopy (EM) and computational modelling to understand the impact of diabetes-induced ultrastructural changes on cardiac bioenergetics. We collected transverse micrographs of multiple control and type I diabetic rat cardiomyocytes using EM. Micrographs were converted to finite-element meshes, and bioenergetics was simulated over them using a biophysical model. The simulations also incorporated depressed mitochondrial capacity for oxidative phosphorylation (OXPHOS) and creatine kinase (CK) reactions to simulate diabetes-induced mitochondrial dysfunction. Analysis of micrographs revealed a 14% decline in mitochondrial area fraction in diabetic cardiomyocytes, and an irregular arrangement of mitochondria and myofibrils. Simulations predicted that this irregular arrangement, coupled with the depressed activity of mitochondrial CK enzymes, leads to large spatial variation in adenosine diphosphate (ADP)/adenosine triphosphate (ATP) ratio profile of diabetic cardiomyocytes. However, when spatially averaged, myofibrillar ADP/ATP ratios of a cardiomyocyte do not change with diabetes. Instead, average concentration of inorganic phosphate rises by 40% owing to lower mitochondrial area fraction and dysfunction in OXPHOS. These simulations indicate that a disorganized cellular ultrastructure negatively impacts metabolite transport in diabetic cardiomyopathy. This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.
Publisher: Cold Spring Harbor Laboratory
Date: 09-12-2020
DOI: 10.1101/2020.12.09.416727
Abstract: In a time of rapid environmental change, understanding how the challenges experienced by one generation can influence the fitness of future generations is critically needed. Using tolerance assays, transcriptomic and methylome approaches, we use zebrafish as a model to investigate transgenerational acclimation to hypoxia. We show that short-term paternal exposure to hypoxia endows offspring with greater tolerance to acute hypoxia. We detected two hemoglobin genes that are significantly upregulated by more than 7-fold in the offspring of hypoxia exposed males. Moreover, the offspring which maintained equilibrium the longest showed greatest upregulation in hemoglobin expression. We did not detect differential methylation at any of the differentially expressed genes, suggesting that another epigenetic mechanism is responsible for alterations in gene expression. Overall, our findings suggest that a ‘memory’ of past hypoxia exposure is maintained and that this environmentally induced information is transferred to subsequent generations, pre-acclimating progeny to cope with hypoxic conditions.
Publisher: The Company of Biologists
Date: 14-06-2022
DOI: 10.1242/JEB.242771
Abstract: The anaesthetic isoeugenol has been used as metabolic suppressant for commercial transport of live lobsters in order to decrease energy expenditure and improve survival. Given the central role of mitochondria in metabolism and structural similarities of isoeugenol to the mitochondrial electron carrier coenzyme Q, we explored the influence on mitochondrial function of isoeugenol. Mitochondrial function was measured using high-resolution respirometry and saponin-permeabilised heart fibres from the Australasian red spiny lobster, Jasus edwardsii. Relative to vehicle (polysorbate), isoeugenol inhibited respiration supported by complex I (CI) and cytochrome c oxidase (CCO). While complex II (CII), which also reduces coenzyme Q, was largely unaffected by isoeugenol, respiration supported by CII when uncoupled was depressed. Titration of isoeugenol indicates that respiration through CI has a half-maximal inhibitory concentration (IC50) of 2.4±0.1 µmol l-1, and a full-maximal inhibitory concentration (IC100-) of approximately 6.3 µmol l-1. These concentrations are consistent with those used for transport and euthanasia of J. edwardsii and indicate that CI is a possible target of isoeugenol, like many other anaesthetics with quinone-like structures.
Publisher: Wiley
Date: 09-07-2018
DOI: 10.1002/ECE3.4268
Publisher: The Company of Biologists
Date: 2019
DOI: 10.1242/JEB.191353
Abstract: Exposure to anoxia leads to rapid ATP depletion, alters metabolic pathways and exacerbates succinate accumulation. Upon re-oxygenation, the preferential oxidation of accumulated succinate most often impairs mitochondrial function. Few species can survive prolonged periods of hypoxia and anoxia at tropical temperatures and those that do may rely on mitochondria plasticity in response to disruptions to oxygen availability. Two carpet sharks, the epaulette shark (Hemiscyllium ocellatum ES) and the grey carpet shark (Chiloscyllium punctatum GCS) display different adaptive responses to prolonged anoxia: while the ES enters energy conserving metabolic depression, the GCS temporarily elevates its haematocrit prolonging oxygen delivery. High-resolution respirometry was used to investigate mitochondrial function in the cerebellum, a highly metabolically active organ that is oxygen sensitive and vulnerable to injury after anoxia/re-oxygenation (AR). Succinate was titrated into cerebellar preparations in vitro, with or without pre-exposure to AR, then the activity of mitochondrial complexes was examined. Like most vertebrates, GCS mitochondria significantly increased succinate oxidation rates, with impaired complex I function post-AR. In contrast, ES mitochondria inhibited succinate oxidation rates and both complex I and II capacities were conserved, resulting in preservation of oxidative phosphorylation capacity post-AR. Divergent mitochondrial plasticity elicited by elevated succinate post A/R parallels the inherently ergent physiological adaptations of these animals to prolonged anoxia, namely the absence (GCS) and presence of metabolic depression (ES). Since anoxia tolerance in these species also occurs at temperatures close to that of humans, examining their mitochondrial responses to AR could provide insights for novel interventions in clinical settings.
No related grants have been discovered for Anthony Hickey.