bims-smemid 2023-12-24 papers

Cell Metab. 2023 Dec 14. pii: S1550-4131(23)00449-7. [Epub ahead of print]

Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism.

Riley J Wedan, Jacob Z Longenecker, Sara M Nowinski.

Contrary to their well-known functions in nutrient breakdown, mitochondria are also important biosynthetic hubs and express an evolutionarily conserved mitochondrial fatty acid synthesis (mtFAS) pathway. mtFAS builds lipoic acid and longer saturated fatty acids, but its exact products, their ultimate destination in cells, and the cellular significance of the pathway are all active research questions. Moreover, why mitochondria need mtFAS despite their well-defined ability to import fatty acids is still unclear. The identification of patients with inborn errors of metabolism in mtFAS genes has sparked fresh research interest in the pathway. New mammalian models have provided insights into how mtFAS coordinates many aspects of oxidative mitochondrial metabolism and raise questions about its role in diseases such as obesity, diabetes, and heart failure. In this review, we discuss the products of mtFAS, their function, and the consequences of mtFAS impairment across models and in metabolic disease.

Keywords: fatty acids; inborn errors of metabolism; lipid metabolism; lipids; mitochondria; mitochondrial fatty acid synthesis; mouse models; mtFAS

DOI: https://doi.org/10.1016/j.cmet.2023.11.017

Trends Endocrinol Metab. 2023 Dec 15. pii: S1043-2760(23)00243-6. [Epub ahead of print]

Mitochondrial quality control pathways sense mitochondrial protein import.

Laurie P Lee-Glover, Timothy E Shutt.

Mitochondrial quality control (MQC) mechanisms are required to maintain a functional proteome, which enables mitochondria to perform a myriad of important cellular functions from oxidative phosphorylation to numerous other metabolic pathways. Mitochondrial protein homeostasis begins with the import of over 1000 nuclear-encoded mitochondrial proteins and the synthesis of 13 mitochondrial DNA-encoded proteins. A network of chaperones and proteases helps to fold new proteins and degrade unnecessary, damaged, or misfolded proteins, whereas more extensive damage can be removed by mitochondrial-derived vesicles (MDVs) or mitochondrial autophagy (mitophagy). Here, focusing on mechanisms in mammalian cells, we review the importance of mitochondrial protein import as a sentinel of mitochondrial function that activates multiple MQC mechanisms when impaired.

Keywords: mitochondria; mitochondrial protein import; mitochondrial quality control; mitochondrial unfolded protein response; mitochondrial-derived vesicles; mitophagy

DOI: https://doi.org/10.1016/j.tem.2023.11.004

Int J Mol Sci. 2023 Dec 13. pii: 17423. [Epub ahead of print]24(24):

Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.

Alexander Kalinin, Ekaterina Zubkova, Mikhail Menshikov.

Cellular senescence is a complex process characterized by irreversible cell cycle arrest. Senescent cells accumulate with age, promoting disease development, yet the absence of specific markers hampers the development of selective anti-senescence drugs. The integrated stress response (ISR), an evolutionarily highly conserved signaling network activated in response to stress, globally downregulates protein translation while initiating the translation of specific protein sets including transcription factors. We propose that ISR signaling plays a central role in controlling senescence, given that senescence is considered a form of cellular stress. Exploring the intricate relationship between the ISR pathway and cellular senescence, we emphasize its potential as a regulatory mechanism in senescence and cellular metabolism. The ISR emerges as a master regulator of cellular metabolism during stress, activating autophagy and the mitochondrial unfolded protein response, crucial for maintaining mitochondrial quality and efficiency. Our review comprehensively examines ISR molecular mechanisms, focusing on ATF4-interacting partners, ISR modulators, and their impact on senescence-related conditions. By shedding light on the intricate relationship between ISR and cellular senescence, we aim to inspire future research directions and advance the development of targeted anti-senescence therapies based on ISR modulation.

Keywords: ATF4; ISR; Nrf2; SASP; cellular mechanisms; metabolism; senescence; stress response

DOI: https://doi.org/10.3390/ijms242417423

Anesthesiology. 2023 Dec 20.

Stress pathways induced by volatile anesthetics and failure of preconditioning in a mitochondrial Complex I mutant.

Zachariah P G Olufs, David A Wassarman, Misha Perouansky.

BACKGROUND: Carriers of mutations in the mitochondrial electron transport chain (mETC) are at increased risk of anesthetic-induced neurotoxicity. To investigate the neurotoxicity mechanism and to test preconditioning as a protective strategy, we used a Drosophila melanogaster model of Leigh syndrome. Model flies carried a mutation in ND23 (ND2360114) that encodes an mETC Complex I subunit. We investigated why ND2360114 mutants become susceptible to lethal, oxygen-modulated neurotoxicity within 24 h of exposure to isoflurane but not sevoflurane.METHODS: We used transcriptomics and qRT-PCR to identify genes that are differentially expressed in ND2360114 but not wild type fly heads at 30 min after exposure to high versus low toxicity conditions. We also subjected ND2360114 flies to diverse stressors prior to isoflurane exposure to test whether isoflurane toxicity could be diminished by preconditioning.
RESULTS: The ND2360114 mutation had a greater effect on isoflurane- than sevoflurane-mediated changes in gene expression. Isoflurane and sevoflurane did not affect expression of heat shock protein (Hsp) genes (Hsp22, Hsp27, and Hsp68) in wild type flies, but isoflurane substantially increased expression of these genes in ND2360114 mutant flies. Furthermore, isoflurane and sevoflurane induced expression of oxidative (GstD1and GstD2) and xenobiotic (Cyp6a8 and Cyp6a14) stress genes to a similar extent in wild type flies, but the effect of isoflurane was largely reduced in ND2360114 flies. In addition, activating stress response pathways by preexposure to anesthetics, heat shock, hyperoxia, hypoxia, or oxidative stress did not suppress isoflurane-induced toxicity in ND2360114 mutant flies.
CONCLUSIONS: Mutation of an mETC Complex I subunit generates differential effects of isoflurane and sevoflurane on gene expression that may underlie their differential effects on neurotoxicity. Additionally, the mutation produces resistance to preconditioning by stresses that protect the brain in other contexts. Therefore, Complex I activity modifies molecular and physiological effects of anesthetics in an anesthetic-specific manner.

DOI: https://doi.org/10.1097/ALN.0000000000004874