Mitochondrial Bioenergetics and Dynamics in Secretion Processes

Cellular senescence is triggered in response to stress stimuli. Agents that damage DNA and strong mitogenic signals, such as the expression of oncogenes or loss of tumor suppressors, are strong senescence inducers (220–223). Senescent cells are characterized by permanent proliferation arrest, activation of the DNA damage response (DDR), increase in size and β-galactosidase activity and acquisition of a secretory phenotype (224, 225). The senescence-associated secretory phenotype (SASP) includes numerous cytokines and chemokines (e.g., IL-1α, IL-1β and IL-6, IL-8), growth factors and extracellular proteases. These mediators can induce senescence in neighboring cells, alter the extracellular matrix, contribute to local inflammation, and recruit immune cells among other effects (226–228); and contribute to several physiological and pathological processes (229, 230). At the transcriptional level most of the SASP components are regulated by NF-κB, C/EBPβ, and NOTCH (231). IL-1β is a component of the SASP that is secreted through unconventional pathways (32). However, many of the SASP factors are most probably secreted through the conventional pathway, though this is practically unexplored.

Several studies support that establishment of senescence and the secretory phenotype is accompanied by metabolic reprogramming including increases in mitochondrial oxygen consumption rates, biogenesis and dynamics. In particular, important alterations have been observed in oncogene and therapy induced senescence (19–21, 232–235). Interestingly replicative senescent cells that present mitochondrial dysfunction (236, 237) secrete lower levels of cytokines and other mediators than oncogene induced senescent cells (20, 224).

Moreover, mitochondria are required to sustain the SASP and mitochondrial depletion down regulates the expression and secretion of multiple cytokines and other factors in senescent cells (21, 26). In oncogene induced senescence inhibition of carnitine palmitoyl transferase I (CPTI), a key enzyme of the mitochondrial fatty acid oxidation pathway, decreases the secretion of several cytokines and growth factors, but not of IL-1β (20). Similar results were obtained upon inhibition of nicotinamide phosphoribosyltransferase (NAMPT), and enzyme from the NAD+ synthesis pathway (25), or silencing of mitochondrial sirtuin 3, known to impair mitochondrial electron transport (26, 238). Silencing of mitochondrial fusion proteins, MFN1 and 2 also impaired the secretion of IL-6 in senescent cells (19). Since mitofusins participate in the tethering of the mitochondria to the ER, these results suggest the association between these two organelles might be relevant in secretion processes in senescence. Finally mitochondrial ROS formation by the ETC (239, 240) and NADPH oxidase 4 (241, 242) are increased in senescent cells, and contribute to the establishment of senescence and the SASP [through the activation of NF-kB (243) and the DDR (244–246)]. Taken together these results point to a link between mitochondrial oxidative metabolism and dynamics and the proinflammatory secretory phenotype.

Since the SASP has been implied in numerous diseases (229, 247), the search for senolytics (that will kill senescent cells) or senomorphics (that will modulate the SASP) has become an active area of research (248, 249). Mitochondria appear as promising targets for the modulation of the SASP in pathological settings were senescent cells are involved.

Herein we present evidence that mitochondria are required for the successful export of proteins to the extracellular space. Mitochondrial dynamics, bioenergetics and distribution as well as their interactions with other organelles, in particular with the ER, can undergo profound changes in response to secretion stimuli. Mitochondria contribute and support the secretion of proteins providing ATP for energy requiring processes, buffering Ca2+ concentrations and offering structural support and signals for NLRP3 inflammasome activation. A better understanding, at the molecular level, of the role of mitochondria in secretion processes is required and will help in the development of new genetic and pharmacological strategies to modulate protein secretion in pathological contexts.

JM, IM, DT, and CQ contributed to the writing of the manuscript, CQ supervised all the activities. JM made the figures. All authors reviewed contents and approved the final version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.