Whitcomb 2023 MiP2023

Whitcomb 2023 MiP2023

Polyunsaturated fatty acid metabolism contributes to age-related impairment of cardiac mitochondrial calcium tolerance.

Link: MiP2023 Obergurgl AT

Whitcomb Luke A (2023)

Event: MiP2023 Obergurgl AT

Authors: Whitcomb Luke A, Li Puma Lance C, Zilhaver PT, Izon CS, Chicco Adam J

Myocardial ischemia causes pathological increases in cardiomyocyte mitochondrial calcium (Ca⁺⁺), which trigger a series of events that contribute to cell death and myocardial necrosis. Previous studies in our lab and others indicate that metabolites of phosholipid-derived arachidonic acid (AA), an omega-6 polyunsaturated fatty acid (PUFA), contribute to mitochondrial permeability transition pore (mPTP) opening in response to Ca⁺⁺ overload, leading to mitochondrial swelling, rupture, and release of reactive oxygen species (ROS) [1,2]. We hypothesized that age-related increases in these parameters result in part from greater mitochondrial production of AA from its abundant membrane PUFA precursor linoleic acid (LA) in response to Ca⁺⁺ overload. To test this hypothesis, we evaluated effects of 50-400 µM Ca⁺⁺ on O₂ consumption, ROS release and mPTP opening in cardiac mitochondria isolated from young (3 mo) and aged (24 mo) BALB/c mice in the presence or absence of an inhibitor of delta-6 desaturase (D6D), the rate-limiting enzyme in AA biosynthesis from LA. Results demonstrate that cardiac mitochondria from old mice release more ROS during oxidative phosphorylation and undergo more mPTP opening in response to Ca⁺⁺ overload than mitochondria from young mice. D6D inhibition significantly attenuates these responses in both young and old mitochondria, but had greater impacts on old, largely abolishing the effect of aging on both ROS release and mPTP opening. Similar attenuation of mPTP opening was seen following inhibition of lipoxygenase enzymes (Baicalein), consistent with the hypothesized links between mitochondrial AA synthesis, eicosanoid production and mPTP in regulating responses of cardiac mitochondria to Ca⁺⁺ overload.

1. Moon SH, Jenkins CM, Liu X, Guan S, Mancuso DJ, Gross RW (2012) Activation of mitochondrial calcium-independent phospholipase A2 gamma by divalent cations mediating arachidonate release and production of downstream eicosanoids. https://10.1074/jbc.M111.336776
2. Moon SH, Jenkins CM, Kiebish MA, Sims HF, Mancuso DJ, Gross RW (2012) Genetic Ablation of Calcium-independent Phospholipase A2γ (iPLA2γ) attenuates calcium-induced opening of the mitochondrial permeability transition pore and resultant cytochrome c. https://doi.org/10.1074/jbc.M112.373654

• Keywords: mitochondrial calcium overload, permeability transition, polyunsaturated fatty acids

• O2k-Network Lab: US CO Fort Collins Chicco AJ

Affiliation

Whitcomb Luke A, Li Puma LC, Zilhaver PT, Izon CS, Chicco AJ

Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA

Corresponding author: [email protected]

Labels:

Organism: Mouse  Tissue;cell: Heart 

Event: Oral