Cellular function requires the coordinated transcription, translocation, and assembly of mitochondrial proteins which are encoded by both the mitochondrial and nuclear genomes. Sexual asymmetry in the transmission of autosomes, sex chromosomes, and the mitochondrial genome complicates predicting the nature of mitochondrial-nuclear interactions. Mitochondrial DNA is present in all offspring but is maternally transmitted, which means selection only acts in females. This allows for the accumulation of sexually antagonistic mitochondrial mutations that are neutral or advantageous in females even if they are deleterious in males. Coined Mother’s Curse, this phenomenon introduces selective pressure for nuclear variants that compensate for this reduction in male fitness, generating a specific subset of mitochondrial- nuclear interactions. While analytical population genetic theory and experimental studies support the existence of these interactions, the factors that influence invasion conditions, their prevalence in natural populations, and the phenotypic consequences of these interactions remain incompletely characterized. Crucially, the chromosomal position of nuclear restorers and the influence their transmission pattern plays on these interactions have not been fully investigated. We expand foundational theory by simulating the dispersal of sexually antagonistic mitochondrial-nuclear interactions dependent on a variety of factors including selection coefficients, genomic location, and sex-determination system to elucidate their evolution over time and their influence on population divergence. In Chapter 2, we start by examining differences within a single population for the dynamics of a single mitochondrial-nuclear interaction dependent on the chromosomal location of nuclear restorers – either autosomal, X-linked, or Y-linked. We find that, in this scenario, Y-linked restorers outperform others in terms of rapidly spreading through a population quickly offsetting the male-harming consequences of Mother’s Curse variants. However, in Chapter 3, when we expand this scenario to not only include multiple mitochondrial-nuclear interactions but also migration between populations, we find that the transmission pattern of Y-linked restorers hinders a population’s ability to rescue male fitness in the face of Mother’s Curse. To further explore mitochondrial-nuclear epistasis, with a focus on mitochondrial-Y interactions, we leverage 36 otherwise isogenic Drosophila melanogaster strains differing only in the geographical origin of their mitochondrial genome and Y chromosome in Chapter 4.