Mitochondria orchestrate proteostatic and metabolic stress responses

Abstract

The eukaryotic cell is morphologically and functionally organized as an interconnected network of organelles that responds to stress and aging. Organelles communicate via dedicated signal transduction pathways and the transfer of information in form of metabolites and energy levels. Recent data suggest that the communication between organellar proteostasis systems is a cornerstone of cellular stress responses in eukaryotic cells. Here, we discuss the integration of proteostasis and energy fluxes in the regulation of cellular stress and aging. We emphasize the molecular architecture of the regulatory transcriptional pathways that both sense and control metabolism and proteostasis. A special focus is placed on mechanistic insights gained from the model organism budding yeast in signaling from mitochondria to the nucleus and how this shapes cellular fitness.

Keywords: mitochondria-to-nucleus signaling; organellar connectivity; protein folding; proteostasis; stress response.

Figure 1. Mitochondria‐to‐nucleus communication pathways

Various signaling routes transmit information from mitochondria to the nucleus in response to disturbances in mitochondrial proteostasis or bioenergetics. Distinct pathways are activated upon compromised protein import, accumulation of mitochondrial proteins, alterations in mitochondrial translation, loss of mitochondrial DNA, impaired respiration, and dissipation of the mitochondrial transmembrane potential and trigger transcriptional reprogramming to adapt cellular proteostasis and metabolism. MTC, mitochondrial translation control; IPTP, interorganellar proteostasis transcription program; UPR^am, unfolded protein response activated by mistargeting of proteins; mitoCPR, mitochondrial compromised protein import response.

Figure 2. Flow through the proteostasis system

The net in‐ and outflow of polypeptides in non‐native conformation determines the state of the proteostasis system. Newly synthesized proteins exiting the ribosome as well as misfolded proteins constitute the major inflow, while organellar import of newly synthesized peptides (e.g., into the ER and mitochondria) and protein folding as well as proteolytic degradation represent the main outflow from the cytosolic proteostasis system.

Figure 3. Transcriptional reprogramming in response to alterations of the mitochondrial translation machinery

Modifications in mitochondrial translation or mitoribosome composition trigger distinct transcriptional changes that impact aging. The absence of the mitoribosomal subunit Afo1 activates mitochondrial back‐signaling involving the transcription factor Sfp1, an essential regulator of cytosolic translation. The loss of mitochondrial translation control, e.g., in the absence of Sov1, impacts on PKA signaling and the Msn2/4 stress response and activates Sir2‐mediated gene silencing. Mutations that alter the accuracy of mitochondrial translation trigger transcriptional changes via the Msn2/4 stress signaling pathway that affect cellular proteostasis and aging.

Figure 4. Transcriptional responses to metabolic stress

Cells adjust gene expression to the availability of energy sources to maintain optimal fluxes through fermentation and respiration. These metabolic transcriptional pathways have overlapping genetic targets with pathways responding to proteotoxic stress. Top: The retrograde response is activated upon compromised mitochondrial energy metabolism. Binding of Mks1 to Rtg2 allows the heterodimeric transcription factors Rtg1 and Rtg3 to escape latency control and to translocate to the nucleus to activate the retrograde response genes. In addition, TORC1 signaling as well as Ras2/PKA signaling impacts on the retrograde response. Left: The phosphatase Aup1, a regulator of mitophagy, is required for an efficient induction of the retrograde response in aged cells, connecting mitophagic protein quality control to the retrograde response‐induced transcriptional reprogramming. Bottom: The PKA‐Msn2/4 regulon integrates metabolic and proteostatic cues into a broad transcriptional program that enables cells to adapt to starvation and stress.