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Towards a Systems Biology View of Mitochondria in the Animal Production Industries
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Abstract
The mitochondria are largely responsible for converting the chemical energy derived from animal feed into the biologically usable form of intracellular ATP. The energy liberated during the subsequent hydrolysis of the ATP pool ‘foots the bioenergetic bill’ that underpins all manner of commercial traits. Because mitochondrial function is conserved across the Eukaryotes, this energy transformation is relevant to all farm species and all production systems. Particular interest has been directed towards understanding the cellular basis of the overtly bioenergetic whole animal phenotypes, especially feed efficiency. However, mitochondrial associations have also been identified for a range of other live animal, carcass, and meat quality traits.
The mitochondrion is challenging to model. It is composed of ~1500 proteins derived from two structurally independent yet co-ordinately regulated genomes. Its various biological functions, of which aerobic combustion of feed energy is just one, are a product of mitochondrial content and mitochondrial activity. Mitochondrial content is dramatically expanded in circumstances of high energetic demand. For example, the pectoralis muscle of a hummingbird boasts a tissue mitochondrial content (35%) ~10-fold higher than that of sedentary but extremely feed efficient broiler chickens (2-4%).
With a view to determining functional variation across populations of farm animals, we have developed high throughput molecular assays for estimating individual mtDNA copy number (as a proxy for tissue mitochondrial content) in broilers, sheep, and cattle. In broilers we found 1) systemic regulation across the musculature and 2) negative correlations of mitochondrial content with muscle mass. Similarly, in sheep we have found 1) systemic regulation in digestive tissue and liver and 2) that liver is the tissue whose content is most responsive to caloric intake.
Mitochondrial activity on the other hand can be approximated by measuring oxygen consumption. Unlike content, which takes months to adjust (e.g. the gradual training effect resulting from an endurance regimen), activity can alter over a few seconds (e.g. oxygen consumption at rest versus exercise). We have found that cultured peripheral blood mononuclear cells from horses seropositive for Ross River virus infection have impaired metabolic flux on a per unit mitochondrial basis but restore overall cellular performance via a compensatory increase in mitochondrial content.
A second challenge with understanding function lies in interpreting ‘omics’ data sets. For example, one study found that in rumen epithelia of steers the most feed efficient individuals had higher expression of mRNA-encoding mitochondrial proteins but lower mtDNA copy numbers. Given these challenges, we advocate measuring mitochondrial function at multiple levels of biological organisation.
As part of a strategy to better understand mitochondrial function, we have reconstructed a high-resolution co-expression network comprising 872 nodes and 12,445 edges. The network was based on publicly available data from the Cattle Gene Atlas comprising 723 RNA-seq libraries across 91 tissues from 447 individuals. Cluster analysis identified discrete modules reflecting the mtDNA genome, and those encoded proteins localising to the matrix and the inner mitochondrial membrane, respectively. This mitochondrial network can be used as a framework for interpreting molecular measurements from any tissue of any farm species.