The emergence of the mitochondrial genome as a partial regulator of nuclear function is providing new insights into the genetic mechanisms underlying age-related complex disease

Abstract

Mitochondrial malfunction appears to be intimately associated with age and age-related complex disorders but the precise pathological relevance of such malfunction remains unclear. Mitochondrial, and more specifically bioenergetic, malfunction is commonly encountered in cancer, degenerative disorders and aging. The identification of a mitochondrial-nuclear retrograde signaling pathway in yeast has facilitated the study of the corresponding retrograde signaling mechanisms induced in response to mitochondrial malfunction in mammals including human. Mitochondrial-nuclear crosstalk is critical for the maintenance of cellular homeostasis, and some mitochondrial DNA mutations may perturb crosstalk signaling. However, ascertaining whether mitochondrial malfunction is a cause or a consequence of disease development will be key to determining whether or not impaired crosstalk signaling is of direct pathological and hence therapeutic relevance. Here, we review what is known about the nuclear adaptive compensatory mechanisms induced in response to mitochondrial malfunction. We discuss the role of mitochondrial DNA variants in modulating the penetrance of human inherited disease caused by mutations in the nuclear genome and explore the underlying mechanisms by which they influence the retrograde response. We conclude that mitochondrial DNA variants have the potential to induce molecular signals through the mitochondrial-nuclear crosstalk mechanism, thereby promoting nuclear compensation in response to mitochondrial malfunction. The implications for the development of genetic or pharmaceutical interventions for the treatment of mitochondrial malfunction in complex disease are also explored.

Mitochondrial Genomic Backgrounds Affect Nuclear DNA Methylation and Gene Expression

“…Mitochondria-directed changes in nuclear gene function (17) are presumably related to a mitochondrion’s role in generating and regulating high energy molecules, such as ATP, acetyl-CoA, and alpha-ketoglutarate. Changes in nuclear gene expression reciprocally signal the mitochondrial genome (18, 19), regulating mitochondrial mass, bioenergetic state and redox potential (20).…”

“…Most knowledge of retrograde signaling comes from studies performed in S. cerevisiae , where it has been shown that key regulatory pathways are dependent upon retrograde signaling (21, 22). Studies of this type have led to hypotheses that disruptions or mutations in one genome can result in epigenetic changes in the other genome (17). …”

Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells

“…Mitochondrial–nuclear crosstalk is critical for the maintenance of cellular homeostasis and is dysregulated in cancer (6). Epithelial tumor cell metabolism is supported by fuel sources from cancer-associated fibroblasts and adipocytes (7).…”

Mitochondrial Aging: Focus on Mitochondrial DNA Damage in Atherosclerosis - A Mini-Review

“…Changes in mitochondria are well known to occur during aging [14,15,16]. The most prominent signs of mitochondrial aging are the structural alterations to this organelle as well as mtDNA damage [17,18,19].…”