life Review Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview Valentina Brillo †, Leonardo Chieregato †, Luigi Leanza *,‡ , Silvia Muccioli ‡ and Roberto Costa ‡ Department of Biology, University of Padova, 35121 Padova, Italy; [email protected] (V.B.); [email protected] (L.C.); [email protected] (S.M.); [email protected] (R.C.) * Correspondence: [email protected]; Tel.: +39-049-827-6343 † These two authors contributed equally. ‡ These authors share senior authorship. 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 Citation: Brillo, V.; Chieregato, L.; Leanza, L.; Muccioli, S.; Costa, R. contribute to the dissection of intracellular molecular mechanisms involved in the pathophysiology Mitochondrial Dynamics, ROS, and of eukaryotic cells, possibly improving future therapeutic approaches. Cell Signaling: A Blended Overview. Life 2021, 11, 332. https://doi.org/ Keywords: mitochondrial dynamic; cell signaling; ROS; cancer 10.3390/life11040332 Academic Editors: Giorgio Lenaz and Salvatore Nesci 1. Introduction Mitochondria are intracellular organelles present in eukaryotic cells that evolutionarily Received: 2 March 2021 originated from symbiotic resident proteobacteria [1]. These organelles are involved in Accepted: 7 April 2021 many cellular functions, such as oxidative phosphorylation, the regulation of cell prolif- Published: 10 April 2021 eration, differentiation, and death. Their different roles in several cellular processes are largely dependent on ATP and reactive oxygen species (ROS) production, both generated Publisher’s Note: MDPI stays neutral during oxidative phosphorylation [2]. Indeed, targeting mitochondrial metabolism with with regard to jurisdictional claims in molecules able to specifically disrupt mitochondrial fitness and trigger cell death has published maps and institutional affil- become a promising strategy against several diseases [3]. iations. Importantly, mitochondria are physically interconnected with other subcellular or- ganelles, such as endoplasmic reticulum (ER), lipid droplets, Golgi apparatus, lysosomes, melanosomes, and peroxisomes [4]. Indeed, mitochondria–organelle contact sites represent real signaling hubs that are involved in multiple cellular functions, such as lipid trafficking, Copyright: © 2021 by the authors. mitochondrial dynamics, calcium (Ca2+) flow, and ER stress, such that the contacts not only Licensee MDPI, Basel, Switzerland. result in physical but also functional links that finely tune multiple signaling pathways. This article is an open access article Moreover, the capability to establish these interactions with other intracellular or- distributed under the terms and ganelles is strongly dependent on mitochondria’s high attitude to fuse and divide, leading conditions of the Creative Commons Attribution (CC BY) license (https:// to modification of the intracellular mitochondrial network [5]. creativecommons.org/licenses/by/ In addition, ROS figure as byproducts of oxygen consumption and cellular metabolism, 4.0/). and 45% of their total amount is related to mitochondria, specifically to Complex I and Life 2021, 11, 332. https://doi.org/10.3390/life11040332 https://www.mdpi.com/journal/life Life 2021, 11, x FOR PEER REVIEW 2 of 20 Life 2021, 11, 332 In addition, ROS figure as byproducts of oxygen consumption and cellular metabo-2 of 20 lism, and 45% of their total amount is related to mitochondria, specifically to Complex I and Complex III leakage of electrons, which is involved in superoxide (O2−) and hydrogen peroxide (H2O2) production [6]. While ROS production was at first believed to be only − Complexdetrimental III for leakage the cell of electrons,in physiological which cond is involveditions, in the superoxide last two (Odecades,2 ) and it hydrogen has been peroxideconsidered (H that2O2 )its production presence in [6 a]. sublethal While ROS concentration production could was atact first as a believedsecondary to messen- be only detrimentalger that specifically for the modulates cell in physiological distinct cellular conditions, pathways in the [7] lastand two mitochondrial decades, it dynamics has been consideredand morphology that its [8]. presence As a consequence, in a sublethal concentrationROS homeostasis could is act strictly as a secondary regulated messenger by enzy- thatmatic specifically and nonenzymatic modulates mechanisms, distinct cellular with pathways the aim [of7] maintaining and mitochondrial balance dynamics among ROS and morphologyproduction and [8]. scavenging As a consequence, [9]. Once ROS this homeostasis critical equilibrium is strictly regulatedis impaired, by enzymaticROS overload and nonenzymaticis one of the main mechanisms, players in withthe onset the aim of a of pl maintainingethora of different balance diseases, among including ROS production cancer and[6], where scavenging it exerts [9]. a Oncedual regulation, this critical influencing equilibrium cell is impaired,survival and ROS oxidative overload stress, is one leading of the mainto cell players death, as in well the onset as mediating of a plethora redox of sign differentaling events diseases, beneficial including for cancer the progression [6], where of it exerts a dual regulation, influencing cell survival and oxidative stress, leading to cell death, the disease [9]. as well as mediating redox signaling events beneficial for the progression of the disease [9]. In this review, we describe the known signaling pathways mediated by mitochon- In this review, we describe the known signaling pathways mediated by mitochondrial drial structure rearrangements or by mitochondrial ROS release, focusing also on possible structure rearrangements or by mitochondrial ROS release, focusing also on possible therapeutic targets against disease formation. therapeutic targets against disease formation. 2. Mitochondrial Dynamics: A Multiplayer Regulation Proper mitochondrialmitochondrial integrityintegrity andand physiologyphysiology is is essential essential for for cell cell homeostasis. homeostasis. Mito- Mi- chondrialtochondrial fusion fusion and and fission fission dynamics, dynamics, organelle organelle transport, transport, mitophagy,mitophagy, interactioninteraction withwith other organelles, such as the endoplasmic re reticulumticulum (ER) and the cytoskeleton, and ge- nomic mitochondrial control are only a few of thethe severalseveral mechanismsmechanisms involvedinvolved in thethe fitnessfitness of these fundamental organelles. Thus, the improper surveillance on mitochondrial dynamics andand partitioningpartitioning on on daughter daughter cells cell cans can give give rise rise to a wideto a wide spectrum spectrum of syndromes of syn- anddromes diseases and diseases [5]. [5]. Focusing on the fusion and fissionfission processes,processes, these are mainly regulated by proteins belonging to the dynamin-related family of largelarge GTPases that utilize GTP hydrolysishydrolysis toto drive mechanical work on biological membranes (Figure(Figure1 1))[ 10[10].]. Figure 1. Modulation of fusion and fissionfission processes. Left panel: the endoplasmic reticulumreticulum is wrapping the mitochondria inin thethe sitesite ofof fission,fission, wherewhere polymerspolymers ofof dynamin-relateddynamin-related proteinprotein 1 (DRP1)(DRP1) (main(main interactorinteractor inin thethe fissionfission process)process) areare present.present. Right panel: the two different eventsevents ofof outerouter mitochondrialmitochondrial membranemembrane (OMM)(OMM) fusionfusion andand innerinner mitochondrialmitochondrial membrane (IMM) fusion are separately shown. Essentials components for OMM fusion are Mitofusins. In the IMM fusion 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. Life 2021, 11, 332 3 of 20 The membrane potential is also a crucial player in the mitochondrial fission process, by triggering dynamin-related protein 1 (DRP1) activity [11,12]. DRP1 translocates from the cytoplasm to the outer mitochondrial membrane (OMM) via a physical interaction with several adapter proteins, such as mitochondrial