Mitochondrial Transfer in Cancer: A Comprehensive Review

Abstract

Depending on their tissue of origin, genetic and epigenetic marks and microenvironmental influences, cancer cells cover a broad range of metabolic activities that fluctuate over time and space. At the core of most metabolic pathways, mitochondria are essential organelles that participate in energy and biomass production, act as metabolic sensors, control cancer cell death, and initiate signaling pathways related to cancer cell migration, invasion, metastasis and resistance to treatments. While some mitochondrial modifications provide aggressive advantages to cancer cells, others are detrimental. This comprehensive review summarizes the current knowledge about mitochondrial transfers that can occur between cancer and nonmalignant cells. Among different mechanisms comprising gap junctions and cell-cell fusion, tunneling nanotubes are increasingly recognized as a main intercellular platform for unidirectional and bidirectional mitochondrial exchanges. Understanding their structure and functionality is an important task expected to generate new anticancer approaches aimed at interfering with gains of functions (e.g., cancer cell proliferation, migration, invasion, metastasis and chemoresistance) or damaged mitochondria elimination associated with mitochondrial transfer.

Keywords: cancer; cancer metabolism; chemoresistance; metastasis; mitochondria; mitochondrial transfer; oxidative phosphorylation (OXPHOS); reactive oxygen species (ROS); tricarboxylic acid (TCA) cycle; tunneling nanotubes (TNT).

Figure 1

Mechanisms of formation of TNT and detail of intercellular mitochondria transfer. (A) TNTs can be formed by cell dislodgment, when cells are close together and move apart, creating TNTs that can be either open-ended or close-ended. (B,C) TNTs can occur by the extension of membrane protrusion(s) from one cell (B) or from both cells (C), and can be open-ended or close-ended. (D) Damage-inducing events can trigger the transfer of healthy mitochondria from healthy cells to damaged cells.