bims-smemid 2024-05-19 papers

on Stress metabolism in mitochondrial dysfunction

Issue of 2024–05–19
eight papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines

The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration.
The Blood-Brain Barrier Is Unaffected in the Ndufs4-/- Mouse Model of Leigh Syndrome.
Unexpected roles for AMPK in the suppression of autophagy and the reactivation of MTORC1 signaling during prolonged amino acid deprivation.
The role of brown adipose tissue in metabolic health.
The lactate wasteland.
Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission.
AMPK as a mediator of tissue preservation: time for a shift in dogma?
Mitochondrial Dysfunction: A Roadmap for Understanding and Tackling Cardiovascular Aging.

Aging Cell. 2024 May 16. e14165

The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration.

Mohamed Ariff Iqbal, Maria Bilen, Yubing Liu, Vanessa Jabre, Bensun C Fong, Imane Chakroun, Smitha Paul, Jingwei Chen, Steven Wade, Michel Kanaan, Mary-Ellen Harper, Mireille Khacho, Ruth S Slack.

  Impaired mitochondrial function is a hallmark of aging and a major contributor to neurodegenerative diseases. We have shown that disrupted mitochondrial dynamics typically found in aging alters the fate of neural stem cells (NSCs) leading to impairments in learning and memory. At present, little is known regarding the mechanisms by which neural stem and progenitor cells survive and adapt to mitochondrial dysfunction. Using Opa1-inducible knockout as a model of aging and neurodegeneration, we identify a decline in neurogenesis due to impaired stem cell activation and progenitor proliferation, which can be rescued by the mitigation of oxidative stress through hypoxia. Through sc-RNA-seq, we identify the ATF4 pathway as a critical mechanism underlying cellular adaptation to metabolic stress. ATF4 knockdown in Opa1-deficient NSCs accelerates cell death, while the increased expression of ATF4 enhances proliferation and survival. Using a Slc7a11 mutant, an ATF4 target, we show that ATF4-mediated glutathione production plays a critical role in maintaining NSC survival and function under stress conditions. Together, we show that the activation of the integrated stress response (ISR) pathway enables NSCs to adapt to metabolic stress due to mitochondrial dysfunction and metabolic stress and may serve as a therapeutic target to enhance NSC survival and function in aging and neurodegeneration.

Keywords:  Hypoxia; Opa1; adult neurogenesis; intergrated stress response; metabolic adaptation; mitochondrial dynamics; neurodegeneration

DOI:  https://doi.org/10.1111/acel.14165
Int J Mol Sci. 2024 Apr 29. pii: 4828. [Epub ahead of print]25(9):

The Blood-Brain Barrier Is Unaffected in the Ndufs4-/- Mouse Model of Leigh Syndrome.

Robin Reynaud-Dulaurier, Romain Clément, Sara Yjjou, Cassandra Cresson, Yasmina Saoudi, Mathilde Faideau, Michael Decressac.

  Mitochondrial dysfunction plays a major role in physiological aging and in many pathological conditions. Yet, no study has explored the consequence of primary mitochondrial deficiency on the blood-brain barrier (BBB) structure and function. Addressing this question has major implications for pharmacological and genetic strategies aimed at ameliorating the neurological symptoms that are often predominant in patients suffering from these conditions. In this study, we examined the permeability of the BBB in the Ndufs4-/- mouse model of Leigh syndrome (LS). Our results indicated that the structural and functional integrity of the BBB was preserved in this severe model of mitochondrial disease. Our findings suggests that pharmacological or gene therapy strategies targeting the central nervous system in this mouse model and possibly other models of mitochondrial dysfunction require the use of specific tools to bypass the BBB. In addition, they raise the need for testing the integrity of the BBB in complementary in vivo models.

Keywords:  AAV vector; Leigh syndrome; blood–brain barrier; mitochondrial diseases

DOI:  https://doi.org/10.3390/ijms25094828
Autophagy. 2024 May 14.

Unexpected roles for AMPK in the suppression of autophagy and the reactivation of MTORC1 signaling during prolonged amino acid deprivation.

Dubek Kazyken, Sydney G Dame, Claudia Wang, Maxwell Wadley, Diane C Fingar.

  AMPK promotes catabolic and suppresses anabolic cell metabolism to promote cell survival during energetic stress, in part by inhibiting MTORC1, an anabolic kinase requiring sufficient levels of amino acids. We found that cells lacking AMPK displayed increased apoptotic cell death during nutrient stress caused by prolonged amino acid deprivation. We presumed that impaired macroautophagy/autophagy explained this phenotype, as a prevailing view posits that AMPK initiates autophagy (often a pro-survival response) through phosphorylation of ULK1. Unexpectedly, however, autophagy remained unimpaired in cells lacking AMPK, as monitored by several autophagic readouts in several cell lines. More surprisingly, the absence of AMPK increased ULK1 signaling and MAP1LC3B/LC3B lipidation during amino acid deprivation while AMPK-mediated phosphorylation of ULK1 S555 (a site proposed to initiate autophagy) decreased upon amino acid withdrawal or pharmacological MTORC1 inhibition. In addition, activation of AMPK with compound 991, glucose deprivation, or AICAR blunted autophagy induced by amino acid withdrawal. These results demonstrate that AMPK activation and glucose deprivation suppress autophagy. As AMPK controlled autophagy in an unexpected direction, we examined how AMPK controls MTORC1 signaling. Paradoxically, we observed impaired reactivation of MTORC1 in cells lacking AMPK upon prolonged amino acid deprivation. Together these results oppose established views that AMPK promotes autophagy and inhibits MTORC1 universally. Moreover, they reveal unexpected roles for AMPK in the suppression of autophagy and the support of MTORC1 signaling in the context of prolonged amino acid deprivation. These findings prompt a reevaluation of how AMPK and its control of autophagy and MTORC1 affect health and disease.

Keywords:  ATG16L1; EIF4EBP1/4EBP1; LC3B; MTOR; RPS6KB1/S6K1; ULK1

DOI:  https://doi.org/10.1080/15548627.2024.2355074
Nat Rev Endocrinol. 2024 May 14.

The role of brown adipose tissue in metabolic health.

Claire Greenhill.

DOI: https://doi.org/10.1038/s41574-024-00999-5
Sci Signal. 2024 May 14. 17(836): eadq3321

The lactate wasteland.

Wei Wong.

Activation of GPR81 in white adipose tissue by lactate results in cancer-associated cachexia.

DOI: https://doi.org/10.1126/scisignal.adq3321
iScience. 2024 May 17. 27(5): 109808

Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission.

Charlène Lhuissier, Valérie Desquiret-Dumas, Anaïs Girona, Jennifer Alban, Justine Faure, Julien Cassereau, Philippe Codron, Guy Lenaers, Olivier R Baris, Naïg Gueguen, Arnaud Chevrollier.

  Mitochondrial dynamics is a process that balances fusion and fission events, the latter providing a mechanism for segregating dysfunctional mitochondria. Fission is controlled by the mitochondrial membrane potential (ΔΨm), optic atrophy 1 (OPA1) cleavage, and DRP1 recruitment. It is thought that this process is closely linked to the activity of the mitochondrial respiratory chain (MRC). However, we report here that MRC inhibition does not decrease ΔΨm nor increase fission, as evidenced by hyperconnected mitochondria. Conversely, blocking F0F1-ATP synthase activity induces fragmentation. We show that the F0F1-ATP synthase is sensing the inhibition of MRC activity by immediately promoting its reverse mode of action to hydrolyze matrix ATP and restoring ΔΨm, thus preventing fission. While this reverse mode is expected to be inhibited by the ATPase inhibitor ATPIF1, we show that this sensing is independent of this factor. We have unraveled an unexpected role of F0F1-ATP synthase in controlling the induction of fission by sensing and maintaining ΔΨm.

Keywords:  Biochemistry; Cell biology; Functional aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2024.109808
Nat Rev Endocrinol. 2024 May 17.

AMPK as a mediator of tissue preservation: time for a shift in dogma?

Henning Tim Langer, Maria Rohm, Marcus DaSilva Goncalves, Lykke Sylow.

Ground-breaking discoveries have established 5'-AMP-activated protein kinase (AMPK) as a central sensor of metabolic stress in cells and tissues. AMPK is activated through cellular starvation, exercise and drugs by either directly or indirectly affecting the intracellular AMP (or ADP) to ATP ratio. In turn, AMPK regulates multiple processes of cell metabolism, such as the maintenance of cellular ATP levels, via the regulation of fatty acid oxidation, glucose uptake, glycolysis, autophagy, mitochondrial biogenesis and degradation, and insulin sensitivity. Moreover, AMPK inhibits anabolic processes, such as lipogenesis and protein synthesis. These findings support the notion that AMPK is a crucial regulator of cell catabolism. However, studies have revealed that AMPK's role in cell homeostasis might not be as unidirectional as originally thought. This Review explores emerging evidence for AMPK as a promoter of cell survival and an enhancer of anabolic capacity in skeletal muscle and adipose tissue during catabolic crises. We discuss AMPK-activating interventions for tissue preservation during tissue wasting in cancer-associated cachexia and explore the clinical potential of AMPK activation in wasting conditions. Overall, we provide arguments that call for a shift in the current dogma of AMPK as a mere regulator of cell catabolism, concluding that AMPK has an unexpected role in tissue preservation.

DOI: https://doi.org/10.1038/s41574-024-00992-y
Aging Dis. 2024 May 11.

Mitochondrial Dysfunction: A Roadmap for Understanding and Tackling Cardiovascular Aging.

Han Zhang, Mairedan Muhetarijiang, Ryan J Chen, Xiaosheng Hu, Jie Han, Liangrong Zheng, Ting Chen.

Cardiovascular aging is a progressive remodeling process constituting a variety of cellular and molecular alterations that are closely linked to mitochondrial dysfunction. Therefore, gaining a deeper understanding of the changes in mitochondrial function during cardiovascular aging is crucial for preventing cardiovascular diseases. Cardiac aging is accompanied by fibrosis, cardiomyocyte hypertrophy, metabolic changes, and infiltration of immune cells, collectively contributing to the overall remodeling of the heart. Similarly, during vascular aging, there is a profound remodeling of blood vessel structure. These remodeling present damage to endothelial cells, increased vascular stiffness, impaired formation of new blood vessels (angiogenesis), the development of arteriosclerosis, and chronic vascular inflammation. This review underscores the role of mitochondrial dysfunction in cardiac aging, exploring its impact on fibrosis and myocardial alterations, metabolic remodeling, immune response remodeling, as well as in vascular aging in the heart. Additionally, we emphasize the significance of mitochondria-targeted therapies in preventing cardiovascular diseases in the elderly.

DOI: https://doi.org/10.14336/AD.2024.0058