bims-smemid 2024-02-11 papers

on Stress metabolism in mitochondrial dysfunction

Issue of 2024–02–11
seven papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines

The molecular mechanism of aging and the role in neurodegenerative diseases.
Function of NAD metabolism in white adipose tissue: lessons from mouse models.
Mitochondrial transfer - a novel promising approach for the treatment of metabolic diseases.
Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency.
Stress Biology: Complexity and Multifariousness in Health and Disease.
Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport.
Drp1-mediated mitochondrial fission promotes pulmonary fibrosis progression through the regulation of lipid metabolic reprogramming by ROS/HIF-1α.

Heliyon. 2024 Jan 30. 10(2): e24751

The molecular mechanism of aging and the role in neurodegenerative diseases.

Juanli Zhao, Zhenjie Han, Li Ding, Ping Wang, Xiutang He, Li Lin.

  Aging is a complex and inevitable biological process affected by a combination of external environmental and genetic factors. Humans are currently living longer than ever before, accompanied with aging-related alterations such as diminished autophagy, decreased immunological function, mitochondrial malfunction, stem cell failure, accumulation of somatic and mitochondrial DNA mutations, loss of telomere, and altered nutrient metabolism. Aging leads to a decline in body functions and age-related diseases, for example, Alzheimer's disease, which adversely affects human health and longevity. The quality of life of the elderly is greatly diminished by the increase in their life expectancy rather than healthy life expectancy. With the rise in the age of the global population, aging and related diseases have become the focus of attention worldwide. In this review, we discuss several major mechanisms of aging, including DNA damage and repair, free radical oxidation, telomeres and telomerase, mitochondrial damage, inflammation, and their role in neurodegenerative diseases to provide a reference for the prevention of aging and its related diseases.

Keywords:  Aging; Anti-Aging; DNA damage; Energy metabolism; Radicals oxidative; Telomere

DOI:  https://doi.org/10.1016/j.heliyon.2024.e24751
Adipocyte. 2024 Feb 05. 2313297

Function of NAD metabolism in white adipose tissue: lessons from mouse models.

So Young Kwon, Yoon Jung Park.

  Nicotinamide adenine dinucleotide (NAD) is an endogenous substance in redox reactions and regulates various functions in metabolism. NAD and its precursors are known for their anti-ageing and anti-obesity properties and are mainly active in the liver and muscle. Boosting NAD+ through supplementation with the precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), enhances insulin sensitivity and circadian rhythm in the liver, and improves mitochondrial function in the muscle. Recent evidence has revealed that the adipose tissue could be another direct target of NAD supplementation by attenuating inflammation and fat accumulation. Moreover, murine studies with genetically modified models demonstrated that nicotinamide phosphoribosyltransferase (NAMPT), a NAD regulatory enzyme that synthesizes NMN, played a critical role in lipogenesis and lipolysis in an adipocyte-specific manner. The tissue-specific effects of NAD+ metabolic pathways indicate a potential of the NAD precursors to control metabolic stress particularly via focusing on adipose tissue. Therefore, this narrative review raises an importance of NAD metabolism in white adipose tissue (WAT) through a variety of studies using different mouse models.

Keywords:  NAD metabolism; NAD supplementation; nicotinamide adenine dinucleotide; nicotinamide phosphoribosyltransferase; white adipose tissue

DOI:  https://doi.org/10.1080/21623945.2024.2313297
Front Endocrinol (Lausanne). 2023 ;14 1346441

Mitochondrial transfer - a novel promising approach for the treatment of metabolic diseases.

Ruijing Chen, Jun Chen.

  Metabolic disorders remain a major global health concern in the 21st century, with increasing incidence and prevalence. Mitochondria play a critical role in cellular energy production, calcium homeostasis, signal transduction, and apoptosis. Under physiological conditions, mitochondrial transfer plays a crucial role in tissue homeostasis and development. Mitochondrial dysfunction has been implicated in the pathogenesis of metabolic disorders. Numerous studies have demonstrated that mitochondria can be transferred from stem cells to pathologically injured cells, leading to mitochondrial functional restoration. Compared to cell therapy, mitochondrial transplantation has lower immunogenicity, making exogenous transplantation of healthy mitochondria a promising therapeutic approach for treating diseases, particularly metabolic disorders. This review summarizes the association between metabolic disorders and mitochondria, the mechanisms of mitochondrial transfer, and the therapeutic potential of mitochondrial transfer for metabolic disorders. We hope this review provides novel insights into targeted mitochondrial therapy for metabolic disorders.

Keywords:  metabolic diseases; mitochondria; mitochondrial transfer; therapy; transplantation

DOI:  https://doi.org/10.3389/fendo.2023.1346441
Hum Mol Genet. 2024 Feb 07. pii: ddae018. [Epub ahead of print]

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency.

Vanitha Nithianandam, Souvarish Sarkar, Mel B Feany.

  Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number of mitochondrial genes, including electron transport chain components, in a large forward genetic screen for mutations causing age-related neurodegeneration in the context of proteostasis dysfunction. We created a model of complex I deficiency in the Drosophila retina to probe the role of protein degradation abnormalities in mitochondrial encephalomyopathies. Using our genetic model, we found that complex I deficiency regulates both the ubiquitin/proteasome and autophagy/lysosome arms of the proteostasis machinery. We further performed an in vivo kinome screen to uncover new and potentially druggable mechanisms contributing to complex I related neurodegeneration and proteostasis failure. Reduction of RIOK kinases and the innate immune signaling kinase pelle prevented neurodegeneration in complex I deficiency animals. Genetically targeting oxidative stress, but not RIOK1 or pelle knockdown, normalized proteostasis markers. Our findings outline distinct pathways controlling neurodegeneration and protein degradation in complex I deficiency and introduce an experimentally facile model in which to study these debilitating and currently treatment-refractory disorders.

Keywords:  Drosophila; complex I deficiency; mitochondria; neurotoxicity; proteostasis

DOI:  https://doi.org/10.1093/hmg/ddae018
Cell Stress Chaperones. 2024 Feb 02. pii: S1355-8145(24)00046-4. [Epub ahead of print]

Stress Biology: Complexity and Multifariousness in Health and Disease.

Matthias P Mayer, Laura Blair, Gregory L Blatch, Thiago J Borges, Ahmed Chadli, Gabriela Chiosis, Aurélie de Thonel, Albena Dinkova-Kostova, Heath Ecroyd, Adrienne L Edkins, Takanori Eguchi, Monika Fleshner, Kevin P Foley, Sotirios Fragkostefanakis, Jason Gestwicki, Pierre Goloubinoff, Jennifer A Heritz, Christine M Heske, Jonathan D Hibshman, Jenny Joutsen, Wei Li, Michael Lynes, Marc L Mendillo, Nahid Mivechi, Fortunate Mokoena, Yuka Okusha, Veena Prahlad, Elizabeth Repasky, Sara Sannino, Federica Scalia, Reut Shalgi, Lea Sistonen, Emily Sontag, Patricija van Oosten-Hawle, Anniina Vihervaara, Anushka Wickramaratne, Shawn Xiang Yang Wang, Tawanda Zininga.

Preserving and regulating cellular homeostasis in the light of changing environmental conditions or developmental processes is of pivotal importance for single cellular and multicellular organisms alike. To counteract an imbalance in cellular homeostasis transcriptional programs evolved, called the heat shock response (HSR), unfolded protein response (UPR) and integrated stress response (ISR), that act cell-autonomously in most cells but in multicellular organisms are subjected to cell-nonautonomous regulation. These transcriptional programs downregulate expression of most genes but increase expression of heat shock genes, including genes encoding molecular chaperones and proteases, proteins involved in repair of stress-induced damage to macromolecules and cellular structures. 61 years after the discovery of the heat shock response by Ferruccio Ritossa many aspects of stress biology are still enigmatic. Recent progress in the understanding of stress responses and molecular chaperones was reported at the 12th International Symposium on Heat Shock Proteins in Biology, Medicine and the Environment in the Old Town Alexandria, VA, USA from 28th to 31st of October 2023.

DOI: https://doi.org/10.1016/j.cstres.2024.01.006
Proc Natl Acad Sci U S A. 2024 Feb 13. 121(7): e2305035121

Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport.

Johan Gustafsson, Jonathan L Robinson, Henrik Zetterberg, Jens Nielsen.

  The energy metabolism of the brain is poorly understood partly due to the complex morphology of neurons and fluctuations in ATP demand over time. To investigate this, we used metabolic models that estimate enzyme usage per pathway, enzyme utilization over time, and enzyme transportation to evaluate how these parameters and processes affect ATP costs for enzyme synthesis and transportation. Our models show that the total enzyme maintenance energy expenditure of the human body depends on how glycolysis and mitochondrial respiration are distributed both across and within cell types in the brain. We suggest that brain metabolism is optimized to minimize the ATP maintenance cost by distributing the different ATP generation pathways in an advantageous way across cell types and potentially also across synapses within the same cell. Our models support this hypothesis by predicting export of lactate from both neurons and astrocytes during peak ATP demand, reproducing results from experimental measurements reported in the literature. Furthermore, our models provide potential explanation for parts of the astrocyte-neuron lactate shuttle theory, which is recapitulated under some conditions in the brain, while contradicting other aspects of the theory. We conclude that enzyme usage per pathway, enzyme utilization over time, and enzyme transportation are important factors for defining the optimal distribution of ATP production pathways, opening a broad avenue to explore in brain metabolism.

Keywords:  ANLS; brain metabolism; genome-scale models; mathematical modeling; metabolism

DOI:  https://doi.org/10.1073/pnas.2305035121
Cell Signal. 2024 Feb 02. pii: S0898-6568(24)00043-3. [Epub ahead of print]117 111075

Drp1-mediated mitochondrial fission promotes pulmonary fibrosis progression through the regulation of lipid metabolic reprogramming by ROS/HIF-1α.

Zhongkai Tong, Xuekui Du, Ying Zhou, Fangxue Jing, JiangPo Ma, Yingying Feng, Saiyun Lou, Qiong Wang, Zhaoxing Dong.

   OBJECTIVE: To confirm the mechanism of dynamic-related protein 1 (Drp1)-mediated mitochondrial fission through ROS/HIF-1α-mediated regulation of lipid metabolic reprogramming in the progression of pulmonary fibrosis (PF).
METHODS: A mouse model of PF was established by intratracheal instillation of bleomycin (BLM) (2.5 mg/kg). A PF cell model was constructed by stimulating MRC-5 cells with TGF-β (10 ng/mL). Pathological changes in the lung tissue and related protein levels were observed via tissue staining. The indicators related to lipid oxidation were detected by a kit, and lipid production was confirmed through oil red O staining. Inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). RT-qPCR, Western blotting and immunofluorescence staining were used to detect the expression of genes and proteins related to the disease. We used CCK-8 and EdU staining to confirm cell proliferation, flow cytometry was used to confirm apoptosis and ROS levels, α-SMA expression was detected by immunofluorescence staining, and mitochondria were observed by MitoTracker staining.
RESULTS: The BLM induced lung tissue structure and alveolar wall thickening in mice. Mitochondrial fission was observed in MRC-5 cells induced by TGF-β, which led to increased cell proliferation; decreased apoptosis; increased expression of collagen, α-SMA and Drp1; and increased lipid oxidation and inflammation. Treatment with the Drp1 inhibitor mdivi-1 or transfection with si-Drp1 attenuated the induction of BLM and TGF-β. For lipid metabolism, lipid droplets were formed in BLM-induced lung tissue and in TGF-β-induced cells, fatty acid oxidation genes and lipogenesis-related genes were upregulated, ROS levels in cells were increased, and the expression of HIF-1α was upregulated. Mdivi-1 treatment reversed TGF-β induction, while H2O2 treatment or OE-HIF-1α transfection reversed the effect of mdivi-1.
CONCLUSION: In PF, inhibition of Drp1 can prevent mitochondrial fission in fibroblasts and regulate lipid metabolism reprogramming through ROS/HIF-1α; thus, fibroblast activation was inhibited, alleviating the progression of PF.

Keywords:  Drp1; HIF-1α; Lipid metabolism; Mitochondrial fission; Pulmonary fibrosis; ROS

DOI:  https://doi.org/10.1016/j.cellsig.2024.111075