The Concerted Action of Mitochondrial Dynamics and Positioning: New Characters in Cancer Onset and Progression

Abstract

Mitochondria are dynamic organelles whose morphology and activity are extremely variable, depending on the metabolic state of the cell. In particular, their shape and movements within the cell are finely regulated by an increasing number of proteins, which take part in the process of mitochondrial fission/fusion and connect the organelles to the cytoskeleton. As to their activities, mitochondria are considered to be at the crossroad between cell life and death since, on the one hand, they are essential in ATP production and in multiple metabolic pathways but, on the other, they are involved in the intrinsic apoptotic cascade, triggered by different stress conditions. Importantly, the process of mitochondrial Ca²⁺ uptake, as well as the morphology and the dynamics of these organelles, is known to deeply impact on both pro-survival and pro-death mitochondrial activities. Recently, increasing evidence has accrued on a central role of deregulated mitochondrial functionalities in the onset and progression of different pathologies, ranging from neurodegenerative diseases to cancer. In this contribution, we will present the latest findings connecting alterations in the machineries that control mitochondrial dynamics and localization to specific cancer hallmarks, highlighting the importance of mitochondria for the viability of cancer cells and discussing their role as promising targets for the development of novel anticancer therapies.

Keywords: cancer; fission; fusion; mitochondria; mitochondrial shape.

Figure 1

The complex and multifaceted relationship between mitochondrial dynamics/positioning and cancer development. (A) The morphology of the mitochondrial network in living cells is the result of the balance between fusion and fission events. The mitochondrial fusion machinery relies on the activity of Mfns and Opa1, while mitochondrial fission is driven by Drp1 in a regulated process that involves other proteins, such as Fis1 and Mff, and endoplasmic reticulum (ER) tubules circumscribing mitochondria. Mitochondrial morphology plays a critical role in overall cell physiology, and changes in mitochondrial shape have been associated with alterations of key physiological processes, such as cell metabolism, proliferation, and migration. (B) Left, Mitochondria fusion promotes the diffusion of metabolites throughout the entire network, sustaining mitochondrial membrane potential, respiration, and metabolism. The propagation of Ca²⁺ waves is also promoted, resulting in a Ca²⁺-dependent apoptosis induction in cancer cells. Right, Mitochondria fragmentation causes an impairment in Ca²⁺ diffusion within the network, which results in an increased resistance of tumor cells to apoptosis, favoring cell proliferation. Lack of mitochondrial fusion also leads to an impaired mtDNA partitioning and accumulation of mtDNA mutations, which could result in mitochondrial metabolic dysfunction. (C) Mitochondrial fission/fusion dynamics have also been reported to impact on the translocation of mitochondria along cytoskeleton to the leading edge of migrating cells. The presence of mitochondria in the cell periphery correlates with the metastatic potential of cancers.