Mitochondrial diseases encompass a broad spectrum of muscular and neurodegenerative disorders, both chronic and progressive, caused by mutations in nuclear (nDNA) or mitochondrial (mtDNA) DNA ^[1][58]. The prevalence of these diseases has been established at 1:5000 ^[2][59]; however, this number is increasing due to the standardization of whole-exome sequencing ^[3][18]. Most OXPHOS disorders in children are a consequence of the mutation of nuclear DNA, and they are transmitted as autosomal recessive traits, usually with severe phenotypes and a fatal outcome. Among the maternally inherited pathogenic mtDNA mutations, more than 50% have been identified in genes encoded by mitochondrial transfer RNAs (mt-tRNA) (MTT genes). At first sight, it might seem paradoxical to induce a mild mitochondria stress in a general mitochondrial dysfunction context; however, recent studies present this strategy as a new alternative treatment for mitochondrial diseases.

Perry et al. showed that the tetracycline antibiotics family increased cell survival and fitness in MELAS cybrids and Rieske cells (Knockout Complex III mouse fibroblasts) under glucose restriction ^[4][60]. Specifically, doxycycline improved survival in wild-type cells treated with piericidin (complex I inhibitor) or antimycin (complex III inhibitor) during glucose deprivation. In addition to tetracyclines, the anti-parasitic agent pentamidine and the antibiotic retapamulin also scored positive on the screening in MELAS and mutant ND1 cybrid cells. They propose a “mitohormetic effect” by the induction of ATF4 (UPR^mt) and p-eIF2α (ISR) as mechanism of action; however, in some cases, cell survival was independent of ATF4, suggesting the high complexity of this pathway. Suarez-Rivero et al. also demonstrated that tetracycline treatment boosts the production of UPR^mt-related proteins and promotes the activation of pathways involving cAMP and cGMP, which might be implicated in mitochondrial compensatory mechanisms comprising sirtuins and chaperones’ activity ^[5][6][7][61,62,63]. Tetracycline treatment and the subsequent activation of UPR^mt, the increased number of chaperones, and mitochondrial auxiliary proteins may promote the stability of a fraction of mutated mitochondrial proteins which would carry out their function to some extent ^[8][64]. All of these antibiotics have one factor in common: they are inhibitors of the mitochondrial translation at different degrees ^[9][10][11][65,66,67].

Given the bacterial origin of mammalian cells’ mitochondria and the fact that they conserve prokaryotic features such as the 55S or 60S ribosomes, it is understandable that mitochondria are exceptionally sensitive to antibiotics ^[12][68]. In this way, mitohormesis can be triggered by a partial inhibition of mitochondrial translation promoting a beneficial retrograde signaling response including the modulation of mitochondrial dynamics, the expression of nuclear and mitochondrial-encoded genes, the antioxidant response, stimulating mitochondrial function, and boosting cellular defense mechanisms that increase stress resistance ^[13][69].

Although the research of Perry et al. and Suarez-Rivero et al. is promising, antibiotic use in mitochondrial diseases is still in debate ^[14][70]. Several antibiotics can worsen the conditions of individuals bearing mtDNA mutations. Aminoglycosides, for instance, induce ototoxic hearing loss in subjects with mutations in the 12S rRNA gene ^[15][71]. Although aminoglycosides typically display specificity toward prokaryotes over eukaryotes, human mitochondrial ribosomes that have A1408 and G1491 at analogous positions exhibit higher resemblance to their bacterial counterparts. This similarity is likely responsible for some of the adverse effects shown by aminoglycosides ^[16][72].

It has recently been demonstrated that pterostilbene in combination with mitochondrial cofactors treatment activates SIRT3 and UPR^mt as compensatory mechanisms, as well as enhances sirtuins’ levels and mitochondrial activity in several cell models of mitochondrial diseases ^[17][73]. In contrast to long-term antibiotic treatment, pterostilbene is considered safe for human consumption and presents numerous well-known features, such as a prominent antioxidant activity and a high anti-inflammatory potential ^[18][74]. Furthermore, it has been reported to prolong lifespan in several animal models ^[19][75] due to its neuroprotective ^[20][76] and cardioprotective ^[21][77] properties. At the molecular level, pterostilbene activates sirtuins ^[19][75] and has been linked to AMP-activated protein kinase (AMPK) ^[22][78] and Nuclear factor erythroid 2-related factor 2 (Nrf2) by recent studies ^[23][79], suggesting that it could be a promising compound to maintain mitochondrial homeostasis.

Neurodegenerative diseases are a widely heterogeneous group of disorders characterized by the progressive degeneration of the structure and function of the central and peripheral nervous system. Although they affect millions of patients worldwide and have a profound impact on families and their community, the pathogenic mechanisms underlying these conditions remain unclear. The therapeutic options for patients are scarce and merely palliative. Nevertheless, there is currently great interest among the scientific community in regard to the identification of biomarkers or concrete genetic mutations that might help clinicians anticipate the onset of these diseases in a way to either treat them when still reversible or slow down their development ^[24][80]. This is especially relevant given the fact that the protein abnormalities that are characteristic of these diseases are present in patients long before the clinical symptoms become noticeable ^[25][26][81,82].

Most neurodegenerative diseases share in common the accumulation of misfolded proteins; however, they also possess traits associated with progressive neuronal dysfunction and death, such as proteotoxic stress, abnormalities in autophagy, neuroinflammation, apoptosis, ROS production, and mitochondrial dysfunction ^[27][83]. Mitochondrial function is of utmost importance for neurons because limited glycolysis causes them to rely exclusively on OXPHOS for energy production. Given that the long neuronal axons require energy transport over long distances, and because synaptic transmission is dependent on calcium signaling, mitochondrial performance needs to be tightly regulated ^[28][84]. Taken together, there is compelling evidence to suggest a relevant mitochondrial involvement in the pathogenesis of several neurodegenerative diseases, with their role being particularly significant in Parkinson’s disease (PD). According to several studies, patients of this condition present a selective deficiency of respiratory chain complex I, which is most remarkable in the substantia nigra ^[29][30][85,86]. In Alzheimer’s diseases (AD), it has been demonstrated that patients present impaired oxygen consumption in the brain, further adding to the notion that bioenergetic dysfunction and mitochondrial impairment are common features ^[31][87]. In fact, impairment of several mitochondrial enzymes has been detected in AD patients, where respiratory chain complex IV is most affected ^[32][88]. Complex IV activity was found to be significantly reduced in the brain tissue of AD patients, which presented a general decrease of electron transport chain function ^[33][89]. Apart from AD and PD, mitochondrial perturbations have been reported in many other neurodegenerative diseases, among which amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) deserve special mention ^[34][90]. Nevertheless, a critical question that remains unanswered is whether mitochondrial dysfunction contributes to the initial stages of neurodegeneration, being primarily responsible for the onset of pathogenesis or just a secondary feature arising from alternative phenomena such as the accumulation of misfolded proteins or cellular stress. Either way, it has been demonstrated that targeting mitochondrial dysfunction is a promising therapeutic strategy for neurodegenerative conditions ^[35][91].

PD is an age-associated neurodegenerative movement disorder that is mainly caused by the death of dopaminergic neurons in the brain substantia nigra ^[36][92]. UPR^mt may regulate the occurrence and development of PD. It has been shown that a PINK1 mutation can activate ATFS-1-dependent UPR^mt and promote dopaminergic neuron survival in a PD worm model ^[37][93]. Ginseng protein protected against neurodegeneration by inducing UPR^mt in a PINK1 fly model of PD ^[38][94]. Dastidar SG et al. demonstrated that activation of 4E-BP1 correlates with UPR^mt induction, which reduces PD associated neurotoxicity in mouse neurons ^[39][95]. In fact, mutant LRRK2^G2019S, the most common PD-causing allele in humans, results in reduced 4E-BP1 function and may contribute to PD pathogenesis by UPR^mt underactivation ^[40][96]. In addition, altered omi and HtrA2 protein, UPR^mt-related proteases, causes neuropathy with the same characteristics as PD ^[41][97].

Alzheimer’s disease (AD) is the most common form of dementia ^[42][98]. Clinically, AD is defined by cognitive impairment that is pervasive enough to interfere with a person’s ability to work or complete daily activities. The main histologic characteristics include amyloid plaques that largely contain amyloid beta (Aβ) protein and neurofibrillary tangles (NFTs) that consist of hyperphosphorylated tau protein, both of which cause premature neuronal death. Current AD treatments confer a slight benefit but ultimately do not prevent progression ^[43][99].

Mitochondria in AD show numerous changes ^[44][100]. First, complex-IV-reduced activity has consistently been observed across numerous tissues. In brain tissue specifically, the decrease in complex IV subunits has been linked with disease progression ^[45][101]. Mitochondrial surface area also decreases, cristae structures are altered, and an increased variability in mitochondrial shape has been observed ^[46][102]. There are changes in fusion and fission mitochondrial proteins that appear to affect mitochondrial localization in AD neurons ^[47][103]. Indeed, neuronal cultures with AD-relevant fission/fusion protein alterations recapitulate AD-like changes in mitochondrial distribution ^[48][104].

Compared to cognitively intact controls, the expression of UPR^mt-related genes is increased by 40–60% in sporadic AD subjects and 70–90% in familial AD, respectively ^[49][105]. Sorrentino et al. showed that increasing mitochondrial proteostasis by targeting mitochondrial translation and mitophagy both pharmacologically and genetically increases the fitness and lifespan of worms, cells, and mouse models of AD and reduces amyloid aggregation ^[50][106]. In addition, UPR^mt is strongly activated and exerts a protective role against Aβ protein toxicity in PITRM1-knockout human cells. In line with this, pharmacological inhibition of UPR^mt exacerbates the Aβ proteotoxicity in PITRM1-knockout human cells ^[51][107]. HConsistereinnt with this study, UPR^mt is activated in the mouse brains and human SHSY5Y cells after Aβ treatment, while the inhibition of UPR^mt aggravates cytotoxic effects of Aβ ^[52][108]. Treatments which increase the NAD+ pool, a sirtuin cofactor, alleviate protein toxicity and improve the memory of AD mouse by activating the UPR^mt. Taken together, these studies provide the evidence of the protective role of UPR^mt on AD. Furthermore, the activation of UPR^mt induced by Aβ may depend on the regulation of two signaling pathways: the mevalonic acid pathway and ceramide pathway ^[53][109]. Therefore, the activation of UPR^mt can relieve the symptoms of AD.

Huntington’s disease (HD) is a fatal and inherited neurodegenerative disorder that progresses for 15–20 years after the initial onset ^[54][110]. The main cause of HD is the expanded CAG repeats encoding polyglutamine (polyQ) in the N-terminus of the huntingtin (Htt) protein ^[55][111]. The genetic cause of HD was identified more than 20 years ago. However, the underlying mechanisms leading to the pathogenesis of HD remain elusive.

Accumulating evidence suggests that mitochondrial dysfunction plays an important role in the pathogenesis of HD ^[56][112]. For instance, mutant Htt associates with the outer mitochondrial membrane in different HD models, resulting in mitochondrial permeability transition pore opening, calcium disturbance, reduced ATP production, mitochondrial membrane potential loss, increased ROS production, and premature release of cytochrome c ^[57][113]. How mutant Htt can affect selectively medium spiny striatal neurons despite its ubiquitous expression is a key question that still remains unanswered. One of the several theories that have been proposed points again to mitochondria, suggesting that medium spiny neurons, characterized by particularly high-energy demands, are especially susceptible to mutant Huntingtin-induced mitochondrial dysfunction and inhibition of respiration ^[58][114].

Fu et al. ^[59][115] found that mutant Htt suppressed the expression of ABCB10, a component of the UPR^{mt [60]}[116], in various HD models by impairing its mRNA stability. Deletion of ABCB10 induced ROS production and cell death in HD mouse striatal cells. Moreover, ABCB10 was required for CHOP activation under mitochondrial stress. They also showed that chaperone HSP60 and protease Clpp, two downstream genes of CHOP ^[61][41], were decreased in HD cells.

Amyotrophic lateral sclerosis (ALS) is caused by the progressive degeneration of motor neurons in the spinal cord, the brain stem, and the motor cortex. Motor neuron death prompts muscle weakness and paralysis, causing death in 1–5 years from the time of symptoms’ onset. The primary identified ALS-linked gene was superoxide dismutase 1 (SOD1), an antioxidant protein ^[62][117]. However, mutations in several other genes have been reported, and various molecular pathways have been associated to neuronal death in ALS ^[63][118]. The only two disease-modifying potential therapies currently approved for ALS are riluzole and edaravone, but the exact neuroprotective action of these drugs is unknown, and they present no obvious improvement in ALS patients’ health ^[64][119]. The absence of alternative drugs for the treatment of ALS indicates the need for the implementation of novel therapeutic strategies

ALS-associated mitochondrial dysfunction comes in many shapes, including defective OXPHOS, ROS production, impaired calcium buffering capacity, and defective mitochondrial dynamics. In addition, mitochondrial dysfunction appears to be directly or indirectly linked to all mechanisms of toxicity associated with ALS, including excitotoxicity, loss of protein homeostasis, and defective axonal transport ^[65][120].

TDP-43 proteinopathy is characterized by the presence of TDP-43 immunoreactive inclusion bodies in the affected tissues. This alteration is present in several neurodegenerative diseases with high predominance in ALS ^[66][67][121,122]. Peng et al. showed that LonP1, one of the key mitochondrial proteases constituting the UPR^mt response, protects against TDP-43-induced cytotoxicity and neurodegeneration. They suggest the activation of LonP1 via UPR^mt as a treatment for TDP-43 proteinopathy, protecting against or reversing mitochondrial damage as a potential therapeutic approach to these neurodegenerative disorders ^[68][123]. Qi et al. demonstrated that the mitochondrial function pathway was disrupted in the brain of SOD1^G93A mice, and the replenishment of intracellular NAD+, by providing nicotinamide, could reduce neurotoxic protein aggregates of mitochondria in the brain of SOD1^G93A mice ^[69][124]. Moreover, they concluded that nicotinamide might modulate mitochondrial proteostasis and improve adult neurogenesis through activation of the UPR^mt signaling in the brain of SOD1^G93A mice. Curiously, it has been reported that UPR^mt is transiently activated in the spinal cord of ALS mice models in the late symptomatic phase. However, there is a significant sex difference in the activation of the UPR^mt: it was significantly activated in female SOD1^G93A mice but not in males ^[70][125]. Finally, Gomez et al. hypothesized that SOD1 may have multiple functions: antioxidant, UPR^mt regulator, and gene transcription enhancer ^[71][126]. Taken together, these functions place SOD1 as a key regulator of the communication between the nucleus and mitochondria.

Maintaining mitochondrial quality in cardiomyocytes is essential, given that they produce 8% of the total ATP consumed by the organism and power the constant contraction and relaxation of the myocardium ^[72][127]. In fact, mitochondrial abnormalities are a common feature to all types of cardiomyopathies ^[73][128]. Mitochondria with aberrant structures are commonly observed in cardiac cells of all forms of heart disease ^[74][129]. Furthermore, cardiomyopathy has been reported due to mitochondrial disease ^[75][130], and mitochondrial dysfunction has been linked with hypertension. It is nowadays clear that the importance of functional mitochondria for cardiac health is undeniable. One of the main mechanisms ensuring mitochondrial fitness is proteostasis. It finetunes biogenesis, folding, and degradation of mitochondrial proteins, processes which are commonly altered during cardiac stress. It has been demonstrated that stimulation of UPR^mt improves mitochondrial function and reduces cardiac damage in response to stress. In this regard, a recent study proved that UPR^mt enhancement with small-molecule agents ameliorates mitochondrial and contractile dysfunction in the murine heart. This is the reason why UPR^mt its wauthors proposed UPR^mt as a potential therapeutic target in heart failure ^[76][131].

Wang et al. demonstrated the relevance of mitophagy and UPR^mt in myocardial injuries and stress ^[77][132]. They proposed UPR^mt activation with oligomycin, a complex V inhibitor, as a mechanism to reduce sepsis-mediated mitochondrial injury and myocardial dysfunction; however, this cardioprotective effect was imperceptible in mitophagy-inhibited mice. On the other hand, when UPR^mt was inhibited, mitophagy-mediated protection of mitochondria and cardiomyocytes was partly blunted. Taken together, their observations suggest that both UPR^mt and mitophagy are slightly activated by myocardial stress and that they work together to sustain mitochondrial performance and cardiac function.

Upregulation of UPR^mt has been proposed as the common pathway in lifespan extension induced by mitochondrial defects ^[78][133]. Studies in C. elegans revealed that the induction of mitochondrial stress at an early age resulted in lifespan extension and UPR^mt upregulation which persisted even after the stress inductor was withdrawn ^[79][134]. This observation suggests that UPR^mt upregulation is directly responsible for lifespan extension in worms. Supporting this idea, Yokoyama et al. demonstrated that transgenic worms expressing the nematode UPR^mt protein Hsp70F live over 40% more than wild-type animals ^[80][135]. To prove whether UPR^mt upregulation also influenced lifespan extension in mammals, a recent study assessed UPR^mt activation in a long-lived mouse model, Snell dwarf mice. These mice have a single point mutation in Pit1 and show more than 40% increase in mean and maximal lifespan ^[81][136]. The results of the study show that UPR^mt was upregulated in both living mice and cultured cells. Moreover, it wahe authors reported that elevated basal and post-stress UPR^mt levels in primary fibroblasts derived from Snell mice. However, at the organismal level, UPR^mt was upregulated only after doxycycline-induced mitochondrial stress exposure ^[82][137].

The ability of UPR^mt activation to prolong lifespan can be explained by several reasons: its positive impact on mitochondrial function, its ability to reduce mitochondrial metabolic by-products, its modulation of insulin/IGF and mTOR signaling, and its involvement in hormetic cellular maintenance ^[83][138]. Following UPR^mt activation, mitochondria undergo structural and functional changes. The mitochondrial network becomes fragmented ^[78][133], and cellular oxygen consumption is significantly reduced ^[84][85][139,140]. This particular phenotype may be a coordinated response to stress that favors mitophagy and lowers respiration to enable mitochondrial repair. Taken together, these measures would ultimately lead to enhanced homeostasis and cell survival, consequently increasing lifespan.

On top of this, UPR^mt is responsible for changes in the production of a series of metabolic by-products with relevant physiological functions. Amidst these, ROS is the most widely studied. It elicits varied cellular stress responses, and by doing so, it influences homeostasis and longevity ^[86][141]. Additionally, the UPR^mt has an impact on the mevalonate pathway, an important target of statins, and on NAD+, which is the substrate for poly (ADP-ribose) polymerases (PARPs) and sirtuin deacetylases and acts as major longevity regulator ^[87][88][56,142]. The link of UPR^mt to longevity might also be explained by its effect on insulin signaling. Reduced insulin/IGF-1 signaling has been directly linked to a series of protective mechanisms such as regulation of endoplasmic reticulum unfolded protein response (UPR^ER) or activation of heat shock factor 1 (HIF-1), which boosts the expression of small heat shock proteins, leading to lifespan extension in worms ^[89][143]. In this line, it has been proven that impairment of the insulin/IGF-1 signaling induces a transient ROS stress signal that potentially activates UPR^mt and results in prolonged lifespan in C. elegans ^[90][144]. Improving the level of cellular NAD⁺ in mice not only increases mitochondrial function but also induces the expression of UPR^mt-associated genes, preventing skeletal muscle stem cells from aging and enhancing life span ^[91][145].

Although several different routes have been proposed to explain UPR^mt implication in longevity, there is the possibility that its lifespan-prolonging ability is the result of improved cellular housekeeping. It is extensively known that loss of proteostasis and the consequent accumulation of misfolded proteins are a fundamental cause of ageing. UPR^mt activation would palliate cellular damage in this context by restoring protein quality control. Not only does it assist correct protein folding via enhancement of chaperones’ expression, but it also promotes refolding of aberrant products and sequestration of protein aggregates in less cytotoxic states ^[92][146].