Lipid Biosynthesis Coordinates a Mitochondrial-to-Cytosolic Stress Response, 2016, Kim et al.

Lipid Biosynthesis Coordinates a Mitochondrial-to-Cytosolic Stress Response
Hyun-Eui Kim; Ana Rodrigues Grant; Milos S. Simic; Rebecca A. Kohnz; Daniel K. Nomura; Jenni Durieux; Celine E. Riera; Melissa Sanchez; Erik Kapernick; Suzanne Wolff; Andrew Dillin

Summary
Defects in mitochondrial metabolism have been increasingly linked with age-onset protein-misfolding diseases such as Alzheimer's, Parkinson's, and Huntington's. In response to protein-folding stress, compartment-specific unfolded protein responses (UPRs) within the ER, mitochondria, and cytosol work in parallel to ensure cellular protein homeostasis. While perturbation of individual compartments can make other compartments more susceptible to protein stress, the cellular conditions that trigger cross-communication between the individual UPRs remain poorly understood.

We have uncovered a conserved, robust mechanism linking mitochondrial protein homeostasis and the cytosolic folding environment through changes in lipid homeostasis. Metabolic restructuring caused by mitochondrial stress or small-molecule activators trigger changes in gene expression coordinated uniquely by both the mitochondrial and cytosolic UPRs, protecting the cell from disease-associated proteins. Our data suggest an intricate and unique system of communication between UPRs in response to metabolic changes that could unveil new targets for diseases of protein misfolding.


Link | PDF (Cell)

 

I expect that lipids would play a role in more than just protein misfolding. Lipids, and other biomolecules, may bond temporarily to other molecules, altering the rate of interactions. For example, if palmitic acid "gets in the way" of an RNA building a protein, that would reduce the rate of production. It's possible that something like butyric acid might temporarily bond with the palmitic acid, reducing its rate of bonding with the RNA. The possibilities for such interactions seems enormous, so it comes down to observing reality: does changing the fatty acid ratios in the diet change the function of a certain type of cell.

My ME is noticeably sensitive to certain fatty acids (and amino acids, and other molecules, and whatever else it takes a fancy to respond to).

 

Abridged selected quotes from introduction —

• The evolution of membrane-enclosed, subcellular structures has given the eukaryotic cell the capacity to maintain distinct microenvironments, facilitating the efficient compartmentalization of processes and regulating the concentration, transport, and diffusion of the thousands of molecules

• Compartmentalization also allows the cell to physically contain its damage, sequestering misfolded proteins and aberrant molecules

• genes and proteins that become differentially regulated upon the application of stress [… are] referred to as an unfolded protein response (UPR)

• cross-communication between compartments is essential for ensuring cellular homeostasis

• Aberrant communication between organelles has been associated with the advent and severity of protein-folding diseases, including neurodegenerative diseases, cardiovascular disease, and diabetes

• Cross-communication between compartments is also critical in the regulation and distribution of lipid stores. Lipid synthesis in the ER and mitochondria is required for the appropriate function across cellular compartments. Importantly, imbalances in lipid stores within individual organelles cause changes in cellular functions across compartments

• Responsibility for the execution of stress responses in individual organelles belongs in part to the Hsp70 family of chaperones, which play a large and central role in the maintenance of cellular protein homeostasis

• roles encompass a wide range of functions, including the folding of newly synthesized proteins, the appropriate translocation and folding of proteins within organelles, and the refolding of aggregating or misfolded proteins […] can be either induced or constitutively expressed. Each of the Hsp70 family members is targeted primarily to a single specific subcellular compartment, such as the mitochondria, cytoplasm, ER

• Within the ER, the Hsp70 chaperones BiP and Hyou1 work in concert to ensure the correct folding of proteins targeted for extracellular secretion.

• Within the mitochondria, the Hsp70 family member mortalin ensures both the translocation and folding of cytosol-synthesized mitochondrial proteins. A loss of Hsp70 function in a specific subcellular compartment will elicit an upregulation of the compartment-specific UPR

• We found that reduced expression of the mitochondrial chaperone hsp-6 (mortalin/Grp75/mtHSP70) is sufficient to induce a previously unidentified mitochondrial-to-cytosolic stress response. We have termed this response the mitochondrial-tocytosolic stress response (MCSR).

• Induction of the MCSR requires the global alteration of fat metabolism: fatty acid synthesis is required for the mitochondrial mediated induction of the MCSR, while the increased synthesis of fatty acids, in contrast, is sufficient to induce the MCSR.
  
• The MCSR accompanies a specific increase in the inhibitors of ceramide synthesis, cardiolipins, indicating that a metabolic shift that involves ceramide levels plays an integral role in MCSR induction

• Collectively, these data support a model in which the cytosol senses mitochondrial stress by recognizing the aberrant intracellular accumulation of lipids or a shift in metabolism, resulting in the upregulation of cross-compartmental defense mechanisms and a reshaping of the protein-folding landscape within the cell.

• results suggest a potential therapeutic effect of fatty acid metabolism in the prevention of protein-misfolding diseases originating from disparate compartments in the cell.

 

Abridged selected quotes from discussion —

• propose a model in which ceramide serves as an inhibitor of MCSR under non-stressed conditions.

• In the presence of stress, such as the reduction of mtHSP70 expression or possibly other forms of severe mitochondrial dysfunction, cardiolipins and other lipids accumulate, acting as inhibitors of ceramide synthesis and shifting the metabolic state of the cell, thereby promoting the induction of the MCSR.

• possible that cardiolipin accumulation serves as an initial signal to activate the MCSR and amplify the lipid biosynthesis signal to maintain the MCSR response

• results suggest a unique mechanism for facilitating crosstalk between mitochondrial and cytosolic stress responses via the re-structuring of fat metabolism

• MCSR is not merely a combination of the UPRmt and HSR but has distinct signaling inputs that require fat accumulation and a dedicated transcriptional circuit that overlaps with both UPR mt and HSR but also has distinct features.

• key metabolic nodes, such as beta-oxidation and lipid accumulation, are central for the coordination of the MCSR. We find that fat accumulation is both necessary and sufficient for induction of the MCSR

• suggests that the MCSR is distinct from a general membrane stress response and might be triggered by causes such as a large change in the protein-folding landscape of the cytoplasm, gross changes in cellular lipid composition, or the presence of as little as a single lipid species or moiety.

• Many of these perturbations also disturb mitochondrial morphology and would be predicted to alter lipid synthesis pathways. These data instead suggest a specific role for mtHSP70 in coordinating cytosolic and mitochondrial homeostasis.

 

Noting in relation to —

Phenotypic characteristics of peripheral immune cells of ME/CFS via transmission electron microscopy: A pilot study (2022)

Metabolomic Evidence for Peroxisomal Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2022)

Metabolic features of chronic fatigue syndrome (2016)