Copper dyshomeostasis and its relationship to AMPK activation, mitochondrial dynamics, and biogenesis of mitochondria: A systematic review of in vivo studies.

Introduction: Copper dyshomeostasis can be related to an increase in copper levels, resulting in toxicity, or to a decrease in tissues levels, impairing cuproenzyme activities. Inside cells, copper can be found in the cytoplasm and inside organelles, and the main organelle that compartmentalizes copper is the mitochondrion. This organelle can form networks and may fuse or fission from this, determining the mitochondrial fusion and fission processes, respectively. Together with mitophagy (autophagy of mitochondria) and mitochondrial biogenesis, mitochondrial fusion and fission (denominated mitochondrial dynamics) determine the number of mitochondria in a cell. A master regulator of mitochondrial dynamics and biogenesis of new mitochondria is AMPK. Considering that both a decrease and an increase in copper levels can influence mitochondrial turnover, especially in diseases related to copper dyshomeostasis, the objective of this systematic review was to verify the current knowledge on the influence of copper homeostasis on AMPK activation, mitochondrial dynamics, and biogenesis of new mitochondria in vivo.

Methods: PubMed (MEDLINE), Embase, and Web of Science databases were used to search for articles in the literature. Data about the effects of a decrease or an increase in copper levels on the expression of proteins involved in mitochondrial dynamics or biogenesis, and data about AMPK and p-AMPK levels were extracted.

Results: Meta-analysis has demonstrated that high copper levels increase mitochondrial fission and inhibit mitochondrial fusion. Additionally, an increase in copper levels results in AMPK activation. Few studies have analyzed the effects of high copper levels on proteins related to mitochondrial biogenesis, as well as the impact of a decrease in this metal on mitochondrial dynamics and biogenesis, and on AMPK activation.

Conclusions: Despite the results gathered in this review, other studies are necessary to completely understand the role of copper in regulating AMPK activation, mitochondrial dynamics, and the biogenesis of new mitochondria, since the cell response to a copper dyshomeostasis could be different depending on the species and tissues analyzed.