Mitochondria are the first-line defense of the cell in the presence of stressing processes that can induce mitochondrial dysfunction. Under these conditions, the activation of two axes is accomplished, namely, (i) the mitochondrial unfolded protein response (UPR) to promote cell recovery and survival of the mitochondrial network; (ii) the mitophagy process to eliminate altered or dysfunctional mitochondria. For these purposes, the former response induces the expression of chaperones, proteases, antioxidant components and protein import and assembly factors, whereas the latter is signaled through the activation of the PINK1/Parkin and BNIP3/NIX pathways. These adaptive mechanisms may be compromised during aging, leading to the development of several pathologies including sarcopenia, defined as the loss of skeletal muscle mass and performance; and non-alcoholic fatty liver disease (NAFLD). These age-associated diseases are characterized by the progressive loss of organ function due to the accumulation of reactive oxygen species (ROS)-induced damage to biomolecules, since the ability to counteract the continuous and large generation of ROS becomes increasingly inefficient with aging, resulting in mitochondrial dysfunction as a central pathogenic mechanism. Nevertheless, the role of the integrated stress response (ISR) involving UPR and mitophagy in the development and progression of these illnesses is still a matter of debate, considering that some studies indicate that the prolonged exposure to low levels of stress may trigger these mechanisms to maintain mitohormesis, whereas others sustain that chronic activation of them could lead to cell death. In this review, we discuss the available research that contributes to unveil the role of the mitochondrial UPR in the development of sarcopenia, in an attempt to describe changes prior to the manifestation of severe symptoms; and in NAFLD, in order to prevent or reverse fat accumulation and its progression by means of suitable protocols to be addressed in future studies.
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http://dx.doi.org/10.3390/ijms21207704 | DOI Listing |
Int J Mol Sci
January 2025
Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
This review describes our current understanding of the role of the mitochondria in the repurposing of the anti-diabetes drugs metformin, gliclazide, GLP-1 receptor agonists, and SGLT2 inhibitors for additional clinical benefits regarding unhealthy aging, long COVID, mental neurogenerative disorders, and obesity. Metformin, the most prominent of these diabetes drugs, has been called the "Drug of Miracles and Wonders," as clinical trials have found it to be beneficial for human patients suffering from these maladies. To promote viral replication in all infected human cells, SARS-CoV-2 stimulates the infected liver cells to produce glucose and to export it into the blood stream, which can cause diabetes in long COVID patients, and metformin, which reduces the levels of glucose in the blood, was shown to cut the incidence rate of long COVID in half for all patients recovering from SARS-CoV-2.
View Article and Find Full Text PDFBiomolecules
November 2024
Department of Cardiology, Hygeia Hospital, 15123 Athens, Greece.
Myocardial cells and the extracellular matrix achieve their functions through the availability of energy. In fact, the mechanical and electrical properties of the heart are heavily dependent on the balance between energy production and consumption. The energy produced is utilized in various forms, including kinetic, dynamic, and thermal energy.
View Article and Find Full Text PDFMol Cells
January 2025
Basic-Clinical Convergence Research Center, School of Biological Sciences, University of Ulsan, Ulsan 44610, Korea. Electronic address:
Eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, which regulates all three unfolded protein response pathways, helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. However, transcriptional regulation of mitochondrial homeostasis by eIF2α phosphorylation during ER stress is not fully understood. Here, we report that the eIF2α phosphorylation-activating transcription factor 4 (ATF4) axis is required for expression of multiple transcription factors (TFs) including nuclear factor erythroid 2-related factor 2 (Nrf2) and their target genes responsible for mitochondrial homeostasis during ER stress.
View Article and Find Full Text PDFEMBO J
January 2025
Department of Oncology, The University of Oxford, Oxford, OX3 7DQ, UK.
Hypoxia is a common feature of solid tumors that has previously been linked to resistance to radiotherapy and chemotherapy, and more recently to immunotherapy. In particular, hypoxic tumors exclude T cells and inhibit their activity, suggesting that tumor cells acquire a mechanism to evade T-cell recognition and killing. Our analysis of hypoxic tumors indicates that hypoxia downregulates the expression of MHC class I and its bound peptides (i.
View Article and Find Full Text PDFJ Hazard Mater
December 2024
School of Medicine, Yunnan University, Kunming 650091, China. Electronic address:
With the increasing incidence of non-hereditary Parkinson's disease (PD), research into the involvement of specific environmental factors, in addition to aging, has become more prominent. The effects of microplastic exposure on public health have gained increased attention as it is known to cause a range of neurotoxic changes, some of which are similar to the pathological features of PD. We carried out low-dose microplastic exposure experiments on mice and Caenorhabditis elegans models and implemented a survey regarding the utilization of plastic products in the population.
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