Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview

Abstract

Mitochondria are key intracellular organelles involved not only in the metabolic state of the cell, but also in several cellular functions, such as proliferation, Calcium signaling, and lipid trafficking. Indeed, these organelles are characterized by continuous events of fission and fusion which contribute to the dynamic plasticity of their network, also strongly influenced by mitochondrial contacts with other subcellular organelles. Nevertheless, mitochondria release a major amount of reactive oxygen species (ROS) inside eukaryotic cells, which are reported to mediate a plethora of both physiological and pathological cellular functions, such as growth and proliferation, regulation of autophagy, apoptosis, and metastasis. Therefore, targeting mitochondrial ROS could be a promising strategy to overcome and hinder the development of diseases such as cancer, where malignant cells, possessing a higher amount of ROS with respect to healthy ones, could be specifically targeted by therapeutic treatments. In this review, we collected the ultimate findings on the blended interplay among mitochondrial shaping, mitochondrial ROS, and several signaling pathways, in order to contribute to the dissection of intracellular molecular mechanisms involved in the pathophysiology of eukaryotic cells, possibly improving future therapeutic approaches.

Keywords: ROS; cancer; cell signaling; mitochondrial dynamic.

Figure 1

Modulation of fusion and fission processes. Left panel: the endoplasmic reticulum is wrapping the mitochondria in the site of fission, where polymers of dynamin-related protein 1 (DRP1) (main interactor in the fission process) are present. Right panel: the two different events of outer mitochondrial membrane (OMM) fusion and inner mitochondrial membrane (IMM) fusion are separately shown. Essentials components for OMM fusion are Mitofusins. In the IMM fusion process, instead, the role of long and short optic atrophy protein 1 (OPA1) is fundamental, as well as their interaction with cardiolipins. Green arrows point out the positive regulators of these processes, whereas the red ones represent the negative modulators.

Figure 2

Mitochondrial reactive oxygen species (ROS) regulation of cellular signaling pathways. Many convergent signaling pathways that contribute to autophagy, proliferation, metastasis, and apoptosis are deeply modulated by an increase in mitochondrial ROS. In blue are depicted several drugs discussed in the text and reported in Table 1, which have been demonstrated to target key mediators of the pathways involved in ROS signaling.

Figure 3

Mitochondrial ROS regulation of cellular processes at a transcriptional level. Antioxidant response, angiogenesis, proliferation, metastasis, and apoptosis are strictly regulated events by an increase in ROS production in the mitochondria (mROS). Indeed, mitochondrial ROS increase promotes the translocation into the nucleus of important factors that possess transcriptional activity, leading to the synthesis of genes related to these main events. In blue, several drugs that target intermediates of different signaling cascades are shown, as reported in Table 1.