mtUPR Modulation as a Therapeutic Target for Primary and Secondary Mitochondrial Diseases.

Mitochondrial dysfunction is a key pathological event in many diseases. Its role in energy production, calcium homeostasis, apoptosis regulation, and reactive oxygen species (ROS) balance render mitochondria essential for cell survival and fitness. However, there are no effective treatments for most primary and secondary mitochondrial diseases to this day. Therefore, new therapeutic approaches, such as the modulation of the mitochondrial unfolded protein response (mtUPR), are being explored. mtUPRs englobe several compensatory processes related to proteostasis and antioxidant system mechanisms. mtUPR activation, through an overcompensation for mild intracellular stress, promotes cell homeostasis and improves lifespan and disease alterations in biological models of mitochondrial dysfunction in age-related diseases, cardiopathies, metabolic disorders, and primary mitochondrial diseases. Although mtUPR activation is a promising therapeutic option for many pathological conditions, its activation could promote tumor progression in cancer patients, and its overactivation could lead to non-desired side effects, such as the increased heteroplasmy of mitochondrial DNA mutations. In this review, we present the most recent data about mtUPR modulation as a therapeutic approach, its role in diseases, and its potential negative consequences in specific pathological situations.

Antioxidants Prevent Iron Accumulation and Lipid Peroxidation, but Do Not Correct Autophagy Dysfunction or Mitochondrial Bioenergetics in Cellular Models of BPAN.

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic disorders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, ß-propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate the autophagic defects and secondary pathological consequences in cellular models derived from two patients harboring WDR45 mutations. Both protein and mRNA expression levels of WDR45 were decreased in patient-derived fibroblasts. In addition, the increase of LC3B upon treatments with autophagy inducers or inhibitors was lower in mutant cells compared to control cells, suggesting decreased autophagosome formation and impaired autophagic flux. A transmission electron microscopy (TEM) analysis showed mitochondrial vacuolization associated with the accumulation of lipofuscin-like aggregates containing undegraded material. Autophagy dysregulation was also associated with iron accumulation and lipid peroxidation. In addition, mutant fibroblasts showed altered mitochondrial bioenergetics. Antioxidants such as pantothenate, vitamin E and α-lipoic prevented lipid peroxidation and iron accumulation. However, antioxidants were not able to correct the expression levels of WDR45, neither the autophagy defect nor cell bioenergetics. Our study demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism and cell bioenergetics. Antioxidants partially improved cell physiopathology; however, autophagy and cell bioenergetics remained affected.

Vitamin E prevents lipid peroxidation and iron accumulation in PLA2G6-Associated Neurodegeneration.

BACKGROUND: PLA2G6-Associated Neurodegeneration (PLAN) is a rare neurodegenerative disease with autosomal recessive inheritance, which belongs to the NBIA (Neurodegeneration with Brain Iron Accumulation) group. Although the pathogenesis of the disease remains largely unclear, lipid peroxidation seems to play a central role in the pathogenesis. Currently, there is no cure for the disease. OBJECTIVE: In this work, we examined the presence of lipid peroxidation, iron accumulation and mitochondrial dysfunction in two cellular models of PLAN, patients-derived fibroblasts and induced neurons, and assessed the effects of α-tocopherol (vitamin E) in correcting the pathophysiological alterations in PLAN cell cultures. METHODS: Pathophysiological alterations were examined in fibroblasts and induced neurons generated by direct reprograming. Iron and lipofuscin accumulation were assessed using light and electron microscopy, as well as biochemical analysis techniques. Reactive Oxygen species production, lipid peroxidation and mitochondrial dysfunction were measured using specific fluorescent probes analysed by fluorescence microscopy and flow cytometry. RESULTS: PLAN fibroblasts and induced neurons clearly showed increased lipid peroxidation, iron accumulation and altered mitochondrial membrane potential. All these pathological features were reverted with vitamin E treatment. CONCLUSIONS: PLAN fibroblasts and induced neurons reproduce the main pathological alterations of the disease and provide useful tools for disease modelling. The main pathological alterations were corrected by Vitamin E supplementation in both models, suggesting that blocking lipid peroxidation progression is a critical therapeutic target.

Coenzyme Q10: Novel Formulations and Medical Trends.

The aim of this review is to shed light over the most recent advances in Coenzyme Q10 (CoQ10) applications as well as to provide detailed information about the functions of this versatile molecule, which have proven to be of great interest in the medical field. Traditionally, CoQ10 clinical use was based on its antioxidant properties; however, a wide range of highly interesting alternative functions have recently been discovered. In this line, CoQ10 has shown pain-alleviating properties in fibromyalgia patients, a membrane-stabilizing function, immune system enhancing ability, or a fundamental role for insulin sensitivity, apart from potentially beneficial properties for familial hypercholesterolemia patients. In brief, it shows a remarkable amount of functions in addition to those yet to be discovered. Despite its multiple therapeutic applications, CoQ10 is not commonly prescribed as a drug because of its low oral bioavailability, which compromises its efficacy. Hence, several formulations have been developed to face such inconvenience. These were initially designed as lipid nanoparticles for CoQ10 encapsulation and distribution through biological membranes and eventually evolved towards chemical modifications of the molecule to decrease its hydrophobicity. Some of the most promising formulations will also be discussed in this review.

Atherosclerosis and Coenzyme Q10.

Atherosclerosis is the most common cause of cardiac deaths worldwide. Classically, atherosclerosis has been explained as a simple arterial lipid deposition with concomitant loss of vascular elasticity. Eventually, this condition can lead to consequent blood flow reduction through the affected vessel. However, numerous studies have demonstrated that more factors than lipid accumulation are involved in arterial damage at the cellular level, such as inflammation, autophagy impairment, mitochondrial dysfunction, and/or free-radical overproduction. In order to consider the correction of all of these pathological changes, new approaches in atherosclerosis treatment are necessary. Ubiquinone or coenzyme Q10 is a multifunctional molecule that could theoretically revert most of the cellular alterations found in atherosclerosis, such as cholesterol biosynthesis dysregulation, impaired autophagy flux and mitochondrial dysfunction thanks to its redox and signaling properties. In this review, we will show the latest advances in the knowledge of the relationships between coenzyme Q10 and atherosclerosis. In addition, as atherosclerosis phenotype is closely related to aging, it is reasonable to believe that coenzyme Q10 supplementation could be beneficial for both conditions.

Two coffins and a funeral: early or late caspase activation determines two types of apoptosis induced by DNA damaging agents.

Cell cytoskeleton makes profound changes during apoptosis including the organization of an Apoptotic Microtubule Network (AMN). AMN forms a cortical structure which plays an important role in preserving plasma membrane integrity during apoptosis. Here, we examined the cytoskeleton rearrangements during apoptosis induced by camptothecin (CPT), a topoisomerase I inhibitor, in human H460 and porcine LLCPK-1α cells. Using fixed and living cell imaging, we showed that CPT induced two dose- and cell cycle-dependent types of apoptosis characterized by different cytoskeleton reorganizations, time-dependent caspase activation and final apoptotic cell morphology. In the one referred as "slow" (~h) or round-shaped, apoptosis was characterized by a slow contraction of the actinomyosin ring and late caspase activation. In "slow" apoptosis the γ-tubulin complexes were not disorganized and microtubules were not depolymerized at early stages. In contrast, "fast" (~min) or irregular-shaped apoptosis was characterized by early caspase activation followed by full contraction of the actinomyosin ring. In fast apoptosis γ-tubulin complexes were disorganized and microtubules were initially depolymerized. However, after actinomyosin contraction, microtubules were reformed adopting a cortical but irregular disposition near plasma membrane. In addition to distinctive cytoskeleton reorganization kinetics, round and irregular-shaped apoptosis showed different biological properties with respect to AMN maintenance, plasma membrane integrity and phagocytes response. Our results suggest that the knowledge and modulation of the type of apoptosis promoted by genotoxic agents may be important for deciding a better therapeutic option and predicting the immune response in cancer treatment.

Dynamic Reorganization of the Cytoskeleton during Apoptosis: The Two Coffins Hypothesis.

During apoptosis, cells undergo characteristic morphological changes in which the cytoskeleton plays an active role. The cytoskeleton rearrangements have been mainly attributed to actinomyosin ring contraction, while microtubule and intermediate filaments are depolymerized at early stages of apoptosis. However, recent results have shown that microtubules are reorganized during the execution phase of apoptosis forming an apoptotic microtubule network (AMN). Evidence suggests that AMN is required to maintain plasma membrane integrity and cell morphology during the execution phase of apoptosis. The new "two coffins" hypothesis proposes that both AMN and apoptotic cells can adopt two morphological patterns, round or irregular, which result from different cytoskeleton kinetic reorganization during the execution phase of apoptosis induced by genotoxic agents. In addition, round and irregular-shaped apoptosis showed different biological properties with respect to AMN maintenance, plasma membrane integrity and phagocyte responses. These findings suggest that knowing the type of apoptosis may be important to predict how fast apoptotic cells undergo secondary necrosis and the subsequent immune response. From a pathological point of view, round-shaped apoptosis can be seen as a physiological and controlled type of apoptosis, while irregular-shaped apoptosis can be considered as a pathological type of cell death closer to necrosis.

Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation.

Primary mitochondrial diseases result from mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) genes, encoding proteins crucial for mitochondrial structure or function. Given that few disease-specific therapies are available for mitochondrial diseases, novel treatments to reverse mitochondrial dysfunction are necessary. In this work, we explored new therapeutic options in mitochondrial diseases using fibroblasts and induced neurons derived from patients with mutations in the GFM1 gene. This gene encodes the essential mitochondrial translation elongation factor G1 involved in mitochondrial protein synthesis. Due to the severe mitochondrial defect, mutant GFM1 fibroblasts cannot survive in galactose medium, making them an ideal screening model to test the effectiveness of pharmacological compounds. We found that the combination of polydatin and nicotinamide enabled the survival of mutant GFM1 fibroblasts in stress medium. We also demonstrated that polydatin and nicotinamide upregulated the mitochondrial Unfolded Protein Response (mtUPR), especially the SIRT3 pathway. Activation of mtUPR partially restored mitochondrial protein synthesis and expression, as well as improved cellular bioenergetics. Furthermore, we confirmed the positive effect of the treatment in GFM1 mutant induced neurons obtained by direct reprogramming from patient fibroblasts. Overall, we provide compelling evidence that mtUPR activation is a promising therapeutic strategy for GFM1 mutations.

Vicious cycle of lipid peroxidation and iron accumulation in neurodegeneration.

Lipid peroxidation and iron accumulation are closely associated with neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases, or neurodegeneration with brain iron accumulation disorders. Mitochondrial dysfunction, lipofuscin accumulation, autophagy disruption, and ferroptosis have been implicated as the critical pathomechanisms of lipid peroxidation and iron accumulation in these disorders. Currently, the connection between lipid peroxidation and iron accumulation and the initial cause or consequence in neurodegeneration processes is unclear. In this review, we have compiled the known mechanisms by which lipid peroxidation triggers iron accumulation and lipofuscin formation, and the effect of iron overload on lipid peroxidation and cellular function. The vicious cycle established between both pathological alterations may lead to the development of neurodegeneration. Therefore, the investigation of these mechanisms is essential for exploring therapeutic strategies to restrict neurodegeneration. In addition, we discuss the interplay between lipid peroxidation and iron accumulation in neurodegeneration, particularly in PLA2G6-associated neurodegeneration, a rare neurodegenerative disease with autosomal recessive inheritance, which belongs to the group of neurodegeneration with brain iron accumulation disorders.

Neurodegeneration, Mitochondria, and Antibiotics.

Neurodegenerative diseases are characterized by the progressive loss of neurons, synapses, dendrites, and myelin in the central and/or peripheral nervous system. Actual therapeutic options for patients are scarce and merely palliative. Although they affect millions of patients worldwide, the molecular mechanisms underlying these conditions remain unclear. Mitochondrial dysfunction is generally found in neurodegenerative diseases and is believed to be involved in the pathomechanisms of these disorders. Therefore, therapies aiming to improve mitochondrial function are promising approaches for neurodegeneration. Although mitochondrial-targeted treatments are limited, new research findings have unraveled the therapeutic potential of several groups of antibiotics. These drugs possess pleiotropic effects beyond their anti-microbial activity, such as anti-inflammatory or mitochondrial enhancer function. In this review, we will discuss the controversial use of antibiotics as potential therapies in neurodegenerative diseases.

Alpha-lipoic acid supplementation corrects pathological alterations in cellular models of pantothenate kinase-associated neurodegeneration with residual PANK2 expression levels.

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) disorders are a group of neurodegenerative diseases that have in common the accumulation of iron in the basal nuclei of the brain which are essential components of the extrapyramidal system. Frequent symptoms are progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. One of the most prevalent subtypes of NBIA is Pantothenate kinase-associated neurodegeneration (PKAN). It is caused by pathogenic variants in the gene of pantothenate kinase 2 (PANK2) which encodes the enzyme responsible for the first reaction on the coenzyme A (CoA) biosynthesis pathway. Thus, deficient PANK2 activity induces CoA deficiency as well as low expression levels of 4'-phosphopantetheinyl proteins which are essential for mitochondrial metabolism. METHODS: This study is aimed at evaluating the role of alpha-lipoic acid (α-LA) in reversing the pathological alterations in fibroblasts and induced neurons derived from PKAN patients. Iron accumulation, lipid peroxidation, transcript and protein expression levels of PANK2, mitochondrial ACP (mtACP), 4''-phosphopantetheinyl and lipoylated proteins, as well as pyruvate dehydrogenase (PDH) and Complex I activity were examined. RESULTS: Treatment with α-LA was able to correct all pathological alterations in responsive mutant fibroblasts with residual PANK2 enzyme expression. However, α-LA had no effect on mutant fibroblasts with truncated/incomplete protein expression. The positive effect of α-LA in particular pathogenic variants was also confirmed in induced neurons derived from mutant fibroblasts. CONCLUSIONS: Our results suggest that α-LA treatment can increase the expression levels of PANK2 and reverse the mutant phenotype in PANK2 responsive pathogenic variants. The existence of residual enzyme expression in some affected individuals raises the possibility of treatment using high dose of α-LA.

Patient-Derived Cellular Models for Polytarget Precision Medicine in Pantothenate Kinase-Associated Neurodegeneration.

The term neurodegeneration with brain iron accumulation (NBIA) brings together a broad set of progressive and disabling neurological genetic disorders in which iron is deposited preferentially in certain areas of the brain. Among NBIA disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by pathologic variants in the PANK2 gene codifying the enzyme pantothenate kinase 2 (PANK2). To date, there are no effective treatments to stop the progression of these diseases. This review discusses the utility of patient-derived cell models as a valuable tool for the identification of pharmacological or natural compounds for implementing polytarget precision medicine in PKAN. Recently, several studies have described that PKAN patient-derived fibroblasts present the main pathological features associated with the disease including intracellular iron overload. Interestingly, treatment of mutant cell cultures with various supplements such as pantothenate, pantethine, vitamin E, omega 3, α-lipoic acid L-carnitine or thiamine, improved all pathophysiological alterations in PKAN fibroblasts with residual expression of the PANK2 enzyme. The information provided by pharmacological screenings in patient-derived cellular models can help optimize therapeutic strategies in individual PKAN patients.

Actin Polymerization Defects Induce Mitochondrial Dysfunction in Cellular Models of Nemaline Myopathies.

Nemaline myopathy (NM) is one of the most common forms of congenital myopathy and it is identified by the presence of "nemaline bodies" (rods) in muscle fibers by histopathological examination. The most common forms of NM are caused by mutations in the Actin Alpha 1 (ACTA1) and Nebulin (NEB) genes. Clinical features include hypotonia and muscle weakness. Unfortunately, there is no curative treatment and the pathogenetic mechanisms remain unclear. In this manuscript, we examined the pathophysiological alterations in NM using dermal fibroblasts derived from patients with mutations in ACTA1 and NEB genes. Patients' fibroblasts were stained with rhodamine-phalloidin to analyze the polymerization of actin filaments by fluorescence microscopy. We found that patients' fibroblasts showed incorrect actin filament polymerization compared to control fibroblasts. Actin filament polymerization defects were associated with mitochondrial dysfunction. Furthermore, we identified two mitochondrial-boosting compounds, linoleic acid (LA) and L-carnitine (LCAR), that improved the formation of actin filaments in mutant fibroblasts and corrected mitochondrial bioenergetics. Our results indicate that cellular models can be useful to study the pathophysiological mechanisms involved in NM and to find new potential therapies. Furthermore, targeting mitochondrial dysfunction with LA and LCAR can revert the pathological alterations in NM cellular models.

Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.

Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.

Modeling Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes Syndrome Using Patient-Derived Induced Neurons Generated by Direct Reprogramming.

Mitochondrial diseases are a heterogeneous group of rare genetic disorders caused by mutations in nuclear or mitochondrial DNA (mtDNA). These diseases are frequently multisystemic, although mainly affect tissues that require large amounts of energy such as the brain. Mutations in mitochondrial transfer RNA (mt-tRNA) lead to defects in protein translation that may compromise some or all mtDNA-encoded proteins. Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS) syndrome is mainly caused by the m.3243A>G mutation in the mt-tRNALeu(UUR) (MT-TL1) gene. Owing to the lack of proper animal models, several cellular models have been developed to study the disease, providing insight in the pathophysiological mechanisms of MELAS. In this study, we show a successful direct conversion of MELAS patient-derived fibroblasts into induced neurons (iNs) for the first time, as well as an electrophysiological characterization of iNs cocultured with astrocytes. In addition, we performed bioenergetics analysis to study the consequences of m.3243A>G mutation in this neuronal model of MELAS syndrome.

Pterostilbene in Combination With Mitochondrial Cofactors Improve Mitochondrial Function in Cellular Models of Mitochondrial Diseases.

Mitochondrial diseases are genetic disorders caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode mitochondrial structural or functional proteins. Although considered "rare" due to their low incidence, such diseases affect thousands of patients' lives worldwide. Despite intensive research efforts, most mitochondrial diseases are still incurable. Recent studies have proposed the modulation of cellular compensatory pathways such as mitophagy, AMP-activated protein kinase (AMPK) activation or the mitochondrial unfolded protein response (UPRmt) as novel therapeutic approaches for the treatment of these pathologies. UPRmt is an intracellular compensatory pathway that signals mitochondrial stress to the nucleus for the activation of mitochondrial proteostasis mechanisms including chaperones, proteases and antioxidants. In this work a potentially beneficial molecule, pterostilbene (a resveratrol analogue), was identified as mitochondrial booster in drug screenings. The positive effects of pterostilbene were significantly increased in combination with a mitochondrial cocktail (CoC3) consisting of: pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid and l-carnitine. CoC3 increases sirtuins' activity and UPRmt activation, thus improving pathological alterations in mutant fibroblasts and induced neurons.

Therapeutic approach with commercial supplements for pantothenate kinase-associated neurodegeneration with residual PANK2 expression levels.

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic disorders frequently associated with iron accumulation in the basal nuclei of the brain characterized by progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. Pantothenate kinase-associated neurodegeneration (PKAN) is one of the most widespread NBIA subtypes. It is caused by mutations in the gene of pantothenate kinase 2 (PANK2) that result in dysfunction in PANK2 enzyme activity, with consequent deficiency of coenzyme A (CoA) biosynthesis, as well as low levels of essential metabolic intermediates such as 4'-phosphopantetheine, a necessary cofactor for essential cytosolic and mitochondrial proteins. METHODS: In this manuscript, we examined the therapeutic effectiveness of pantothenate, panthetine, antioxidants (vitamin E and omega 3) and mitochondrial function boosting supplements (L-carnitine and thiamine) in mutant PANK2 cells with residual expression levels. RESULTS: Commercial supplements, pantothenate, pantethine, vitamin E, omega 3, carnitine and thiamine were able to eliminate iron accumulation, increase PANK2, mtACP, and NFS1 expression levels and improve pathological alterations in mutant cells with residual PANK2 expression levels. CONCLUSION: Our results suggest that several commercial compounds are indeed able to significantly correct the mutant phenotype in cellular models of PKAN. These compounds alone or in combinations are of common use in clinical practice and may be useful for the treatment of PKAN patients with residual enzyme expression levels.

Pantothenate and L-Carnitine Supplementation Improves Pathological Alterations in Cellular Models of KAT6A Syndrome.

Mutations in several genes involved in the epigenetic regulation of gene expression have been considered risk alterations to different intellectual disability (ID) syndromes associated with features of autism spectrum disorder (ASD). Among them are the pathogenic variants of the lysine-acetyltransferase 6A (KAT6A) gene, which causes KAT6A syndrome. The KAT6A enzyme participates in a wide range of critical cellular functions, such as chromatin remodeling, gene expression, protein synthesis, cell metabolism, and replication. In this manuscript, we examined the pathophysiological alterations in fibroblasts derived from three patients harboring KAT6A mutations. We addressed survival in a stress medium, histone acetylation, protein expression patterns, and transcriptome analysis, as well as cell bioenergetics. In addition, we evaluated the therapeutic effectiveness of epigenetic modulators and mitochondrial boosting agents, such as pantothenate and L-carnitine, in correcting the mutant phenotype. Pantothenate and L-carnitine treatment increased histone acetylation and partially corrected protein and transcriptomic expression patterns in mutant KAT6A cells. Furthermore, the cell bioenergetics of mutant cells was significantly improved. Our results suggest that pantothenate and L-carnitine can significantly improve the mutant phenotype in cellular models of KAT6A syndrome.

UPRmt activation improves pathological alterations in cellular models of mitochondrial diseases.

BACKGROUND: Mitochondrial diseases represent one of the most common groups of genetic diseases. With a prevalence greater than 1 in 5000 adults, such diseases still lack effective treatment. Current therapies are purely palliative and, in most cases, insufficient. Novel approaches to compensate and, if possible, revert mitochondrial dysfunction must be developed. RESULTS: In this study, we tackled the issue using as a model fibroblasts from a patient bearing a mutation in the GFM1 gene, which is involved in mitochondrial protein synthesis. Mutant GFM1 fibroblasts could not survive in galactose restrictive medium for more than 3 days, making them the perfect screening platform to test several compounds. Tetracycline enabled mutant GFM1 fibroblasts survival under nutritional stress. Here we demonstrate that tetracycline upregulates the mitochondrial Unfolded Protein Response (UPRmt), a compensatory pathway regulating mitochondrial proteostasis. We additionally report that activation of UPRmt improves mutant GFM1 cellular bioenergetics and partially restores mitochondrial protein expression. CONCLUSIONS: Overall, we provide compelling evidence to propose the activation of intrinsic cellular compensatory mechanisms as promising therapeutic strategy for mitochondrial diseases.

Activation of the Mitochondrial Unfolded Protein Response: A New Therapeutic Target?

Mitochondrial dysfunction is a key hub that is common to many diseases. Mitochondria's role in energy production, calcium homeostasis, and ROS balance makes them essential for cell survival and fitness. However, there are no effective treatments for most mitochondrial and related diseases to this day. Therefore, new therapeutic approaches, such as activation of the mitochondrial unfolded protein response (UPRmt), are being examined. UPRmt englobes several compensation processes related to proteostasis and antioxidant mechanisms. UPRmt activation, through an hormetic response, promotes cell homeostasis and improves lifespan and disease conditions in biological models of neurodegenerative diseases, cardiopathies, and mitochondrial diseases. Although UPRmt activation is a promising therapeutic option for many conditions, its overactivation could lead to non-desired side effects, such as increased heteroplasmy of mitochondrial DNA mutations or cancer progression in oncologic patients. In this review, we present the most recent UPRmt activation therapeutic strategies, UPRmt's role in diseases, and its possible negative consequences in particular pathological conditions.