Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Abstract

Mitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which metabolites are used and processed, notably through the tricarboxylic acid (TCA) cycle. These newly generated metabolites have the capacity to feed other cellular metabolic pathways; modify cellular functions; and, ultimately, generate specific phenotypes. Mitochondria also provide intracellular signaling cues through reactive oxygen species (ROS) production. As expected with such a central cellular role, mitochondrial dysfunctions have been linked to many different diseases. The origins of some of these diseases could be pinpointed to specific mutations in both mitochondrial- and nuclear-encoded genes. In addition to their impressive intracellular tasks, mitochondria also provide intercellular signaling as they can be exchanged between cells, with resulting effects ranging from repair of damaged cells to strengthened progression and chemo-resistance of cancer cells. Several therapeutic options can now be envisioned to rescue mitochondria-defective cells. They include gene therapy for both mitochondrial and nuclear defective genes. Transferring exogenous mitochondria to target cells is also a whole new area of investigation. Finally, supplementing targeted metabolites, possibly through microbiota transplantation, appears as another therapeutic approach full of promises.

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development

“…Both the MT-ND1 (missense m.3460G > A, A52T) and MT-ND2 (m.4776G > A, A103T) mutations are able to form tumors and represent a potential tumorigenic link to cytoplasmic ROS accumulation and HIF-1α stabilization. However, the osteosarcoma cybrids did not form tumors in vivo when the MT-ND1 m.3571insC frameshift mutation induces accumulation of NADH, which, in turn, inhibits α-KG dehydrogenase, leading to increased α-KG and HIF-1α destabilization 2 , 94 .…”

“…The consecutive accumulation of succinate and fumarate result in HIFs stabilization. In the SK-N-BE 2 neuroblastoma cells, fumarate, but not succinate, has been shown to stabilize HIF-1α under normoxic conditions, while both fumarate and succinate induce HIF-2α 86 . Correspondingly, a reduction of transketolase in breast cancer cells leads to decreased HIF-1α by increasing levels of SDH, FH, and MDM2, causing inhibition of tumor metastasis 87 .…”

“…Mitochondria are essential organelles within the cell that regulate cellular energy, metabolism, survival, and proliferation. The mitochondria supply energy in the form of adenosine triphosphate (ATP), the synthesis of which is driven by a proton gradient 1 , 2 , 25 . Mitochondria are also recognized as a metabolic hub as the TCA cycle, which takes place within the mitochondria, coordinates the metabolism of carbohydrates, proteins, and fats into ATP 26 .…”

“…The R22X nonsense SDHD mutation of complex II has been shown to be present in hereditary PGL and PHEO, leading to a loss of complex II activities and succinate accumulation. Succinate has been shown to inhibit the activity of PHD, and it subsequently induces HIF-1α stabilization 2 , 5 . Mitochondrial complex III can sense hypoxic conditions and produce ROS, which stabilizes the HIF-1α protein.…”

“…Mitochondria are essential cellular organelles that play important roles in regulating cellular energy, metabolism, survival, and proliferation 1 , 2 . Furthermore, dysfunction of mitochondria is closely associated with different types of diseases, including cancer 3 .…”