Understanding nuclear compensation to mitochondrial variation, dysfunction, and disease in a new evolutionary mutant model

PROJECT SUMMARY/ABSTRACT
Mitochondria (mt) are responsible for the regulation of essential cellular processes including energy
production, lipid biosynthesis, calcium homeostasis, the cell cycle, cell death, and immunity. Mt regulate
these processes in part using their own genomes (mitogenomes). The mitogenome is small - encoding
only 13 proteins – but the mt proteome is very large including upwards of 2,000 proteins, meaning proper
mt function relies heavily on homeostasis between mito- and nuclear-encoded elements. However,
maintaining mito-nuclear compatibility can be difficult. The mito- and nuclear genomes are inherited
largely independently and the mitogenome evolves approximately 5-10 times faster than the
nuclear genome creating many opportunities for divergent evolution and incompatibility leading to
dysfunction. Mt-dysfunction is common and underlies many prevalent diseases including neuromuscular
degenerative disorders, cancers, and metabolic diseases, yet we have struggled to understand mito-
nuclear dynamics and their impacts on organismal health. This is in part because genomic variation – in
both the nuclear and mitogenomes – can impact severity of mitochondrial dysfunction. Family
members with the same causative mutation, often respond differently to treatments or have differences in
symptoms because of genetic and life history variation. What is needed are studies focused on the
role of genetic variation impacting mito-nuclear dynamics in multiple environments. Accounting for
mitogenomic variation has been a major challenge for two main reasons. First, we are limited in our ability
to edit the mitogenome. Some have been successful editing the mitogenome at low frequency, but we are
not able to ubiquitously edit the mitogenome. Second, most animal models are limited in their
mitogenomic variation. This is often by design in inbred lines, but even outbred models often have minimal
mitogenomic variation. Here we propose the use of specific populations of threespine stickleback fish that
will allow us to fill these gaps. Threespine stickleback are a well-known model for studying genetic
variants underlying complex traits. We have recently characterized the mitogenomic variation across
populations of these fish and have identified mitogenomic divergence that exceeds that of modern
vs ancient humans. Despite this exceptional level of mt variation, there are many populations of fish with
extreme mitogenomic divergence in admixture, generating natural experiments, and unique
opportunities to understand how the nuclear genome is evolving and adapting to maintain
mitogenomic variation. Importantly, the existence of dual marine/freshwater populations of stickleback
with mitogenomic admixture allow us to ask questions about how mt are acting in these different
environments and identify environmentally context-dependent nuclear compensations. This proposal
largely leverages publicly available sequencing data and preserved specimens to fill existing gaps.

Grant Number: 1R21AG087430-01A1
NIH Institute/Center: NIH
Principal Investigator: Emily Beck