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

Abstract

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.

Xbp1 promotes odontoblastic differentiation through modulating mitochondrial homeostasis

“…To examine whether mitochondrial dysfunction plays an essential role in the impaired odontoblastic differentiation potential in the shXbp1 group, we used NR as a therapeutic agent 46 to treat cells of the shXbp1 and NC groups, respectively (Figure 6A). We chose 100 μM as the optimum concentration of NR according to the cell activity measurement under NR treatment with different gradient concentrations (Figure S7).…”

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

“…Three axes of the mtUPR have been described [30]: the transcriptional canonical mtUPR, where ATF4, ATF5, and C/EBP Homologous Protein (CHOP) are the primary effectors; the SIRT3 mtUPR axis, with SIRT3 as the triggering factor; and, thirdly, the intermembrane space mtUPR, which is activated only when mitochondrial stressors are in the mitochondrial intermembrane space, inducing mitochondrial biogenesis via Nrf1 on the one hand and OMI protease on the other [15]. In this work, we focused on the first and second axes since the third is more specific and occurs only when mitochondrial stress is confined to the intermembrane space, whereas in this case, there is stress throughout the mitochondria.…”

“…Originally defined as a transcriptional process, mtUPR upregulated the expression of mitochondrial proteases and chaperones in response to elevated levels of unfolded or misfolded proteins within mitochondria [13]. Over time, this stress response has recently emerged as a potential therapeutic target for a wide selection of diseases, including mitochondrial diseases [8,9,14,15].…”

“…Moreover, an association between mtUPR and mitochondrial biogenesis has been observed in conditions of increased NAD + levels, as this cofactor activates sirtuins. Sirtuins are responsible for the activation of Forkhead box O3 (FOXO3a), a factor involved in mtUPR, and peroxisome proliferator-activated receptor γ co-activator 1α (PGC1α), which participates in mitochondrial biogenesis [15]. The activation of these factors further contributes to the recovery of mitochondrial function.…”

Comprehensive Analysis of Mitochondrial Dynamics Alterations in Heart Diseases

“…Some in vitro stressors (i.e., complex I inhibition, Hsp90 loss of function, unfolded proteins) and in vivo changes in hemodynamic parameters (i.e., pressure overload in HF) trigger the transient activation of mtUPR in the heart. Through a linked nuclear reprogramming, which is induced by mtUPR and largely independent from ATF5, an upregulation of an adaptive gene response is able to restore mitochondrial dysfunctions and cardiac contractility [ 189 , 190 ].…”