Age- and Organ-Specific Differences in Mitochondrial Bioenergetics in Brown Norway Rats.

Jignesh D Pandya,Robert C Macphail,Patrick G Sullivan,Prasada Rao S Kodavanti,Matthew Valdez,Joyce E Royland

doi:10.1155/2020/7232614

Abstract

Mitochondria play a central role in energy homeostasis and act as regulatory checkpoints for downstream metabolic responses and cell senescence processes during an entire life span. Acute or chronic environmental toxicant exposures have shown deleterious organ-specific human health issues at various life stages. Since mitochondria are a prime target for ensuing cellular bioenergetics responses and senescence, it is essential to understand mitochondrial bioenergetic responses in different organs over multiple life stages. Therefore, in the present study, we evaluated mitochondrial bioenergetic parameters in the liver, lung, and heart in four diverse age groups (young: 1 month; adult: 4 months; middle-aged: 12 months; old-aged: 24 month) using male Brown Norway rats as a model of aging (n = 5 sample size/organ/age group) and compared them with our previously published results on brain. Real-time mitochondrial bioenergetic parameters (i.e., State III, State IV, and State V) were measured using the Seahorse Extracellular Flux Analyzer. Additionally, mitochondrial enzyme pyruvate dehydrogenase complex (PDHC), Complex I, Complex II, and Complex IV activities were measured using Synergy HT plate reader. Our results indicated that nearly in all parameters, significant age- and organ-specific interactions were observed. We observed age-specific declines in State III (i.e., ATP synthesis rate) responses in both the heart and lung, where opposite was observed in the liver as age advances. Across the age, the heart has highest enzyme activities than the liver and lung. Interestingly, heart and liver mitochondrial bioenergetic rates and enzyme activities remain higher than the lung, which specifies their higher metabolic capabilities than the lung. Amongst all, bioenergetic rates and enzyme activities in the lung remain lowest suggesting the lung may display higher vulnerability and lower resilience to environmental toxicants during aging than other organs tested here. Overall, these age- and organ-specific findings may facilitate a more contextualized understanding of mitochondrial bioenergetic outcomes when considering the interactions of age-related sensitivities with exposure to chemical stressors from the environment.

Highlights

Mitochondria are known as the “powerhouse” of the cell
Age- and organ-specific differences in mitochondrial bioenergetics were present in most organs
Two-way ANOVA analysis of State III respiration rate (Figure 1(a)), which is related to adenosine triphosphate (ATP) synthesis rate, indicated a significant interaction of age and organ (F9,68 5.822, p 5.612e−6) throughout life stages, with all organs displaying higher average respiration rates compared to lung as determined by post hoc pairwise comparisons. ese differences appear to arise after 1 month in the lung, with all State III respirations rates dropped near to 200 oxygen consumption rates (OCR) as the animal aged. ere was a trend of decreasing State III respiration in the heart, with the largest change observed between 1M and 12 months (12M)

Summary

Introduction

Mitochondria are known as the “powerhouse” of the cell. Metabolic breakdown of complex foods yields glucose, fatty acid, or amino acids via digestion, and these components are further oxidatively metabolized by mitochondria in cells based on energy needs of an organ. E pyruvate dehydrogenase complex (PDHC) enzyme is an entry point of the Krebs cycle where it feeds acetyl groups derived from pyruvate to coenzyme A, thereby initiating cyclic aerobic oxidation of substrates and generating reducing equivalents, i.e., NADH and FADH2. Electrons are transported through Complexes III and IV to the Complex IV as final acceptor of O2 to generate water During this aerobic respiration process, the flow of electrons is coupled to the transfer of protons from the mitochondrial matrix to the intermembrane space and establish the mitochondrial membrane potential (ΔΨm), which is used by Complex V (i.e., ATP synthase) to generate energy in the form of adenosine triphosphate (ATP)

Methods

Results

Conclusion