Increased mitochondrial protein import and cardiolipin remodelling upon early mtUPR

Poveda-Huertes, Daniel; Taşkin, Aslı Aras; Dhaouadi, Ines; Myketin, Lisa; Marada, Adinarayana; Habernig, Lukas; Büttner, Sabrina; Vögtle, F.-Nora

doi:10.1371/journal.pgen.1009664

Cited by 23 publications

(18 citation statements)

References 57 publications

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“…Thus, it is possible that a greater accumulation of misfolded proteins is required to inhibit the mitochondrial import of ATF5 and prompt its nuclear translocation immediately following exercise stress. This is a similar phenomenon to what has been observed in a yeast model, identifying an "early" and "late" UPR mt with diverging efficiencies of mitochondrial protein import depending on the amount of time elapsed post-stress, as well as and the intensity of the stimulus imposed [75]. It is also known that chronically-imposed exercise induces an increase in mitochondrial protein import [76,77].…”

Section: Discussionsupporting

confidence: 80%

ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle

Slavin

Kumari

Hood

2022

Preprint

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ObjectivesThe Mitochondrial Unfolded Protein Response (UPRmt) is a compartment-specific mitochondrial quality control (MQC) mechanism that uses the transcription factor ATF5 to induce the expression of protective enzymes to restore mitochondrial function. Acute exercise is a stressor that has the potential to temporarily disrupt organellar protein homeostasis, however, the roles of ATF5 and the UPRmt in maintaining basal mitochondrial content, function and exercise-induced MQC mechanisms in skeletal muscle are not known.MethodsATF5 KO and WT mice were examined at rest or after a bout of acute endurance exercise. We measured protein content in whole muscle, nuclear, cytosolic and mitochondrial fractions, in addition to mRNA transcript levels in whole muscle. Using isolated mitochondria, we quantified rates of oxygen consumption and ROS emission to observe the effects of the absence of ATF5 on organelle function.ResultsATF5 KO mice exhibited a larger and less functional muscle mitochondrial pool, most likely a culmination of enhanced biogenesis via increased PGC-1α expression, and attenuated mitophagy. The absence of ATF5 resulted in a reduction in antioxidant proteins and increases in mitochondrial ROS emission, cytosolic cytochrome c, and the expression of mitochondrial chaperones. KO muscle also displayed enhanced exercise-induced stress kinase signaling, but a blunted mitophagic and UPRmt gene expression response, complemented by significant increases in the basal mRNA abundance and nuclear localization of ATF4. Instead of promoting its nuclear translocation, acute exercise caused the enrichment of ATF5 in mitochondrial fractions. We also identified PGC-1α as an additional regulator of the basal expression of UPRmt genes.ConclusionThe transcription factor ATF5 retains a critical role in the maintenance of mitochondrial homeostasis and the appropriate response of muscle to acute exercise for the optimization of mitochondrial quality control.Graphical abstractA modified version of the schematic shown in Fig. 8 will be supplied at a later time.

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Section: Discussionsupporting

confidence: 80%

ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle

Slavin

Kumari

Hood

2022

Preprint

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“…Increased levels of TOMM22 may enhance formation of the TOM complex and facilitate protein import into mitochondria to partially alleviate the mitochondrial damage induced by TMEM160 depletion. Indeed, a recent study reported that mitochondrial protein import is enhanced at an early stage of the UPR mt [26]. Thus, TMEM160 depletion may result in important but not strong upregulation of the UPR mt and TOMM22 to prevent mitochondrial damage.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of TMEM160 leads to an increase in reactive oxygen species generation and the induction of the mitochondrial unfolded protein response

2022

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Transmembrane protein 160 (TMEM160) was recently reported to be localized to the mitochondrial inner membrane, but mitochondrial function was noted to be unaffected by loss of TMEM160. In contrast to these previously published findings, we report here that the absence of TMEM160 influences intracellular responses. After confirming that TMEM160 is localized in the inner mitochondrial membrane, we knocked down TMEM160 in human cultured cells and analyzed the changes in cellular responses. TMEM160 depletion led to an upregulation of the mitochondrial chaperone HSPD1, suggesting that depletion induced the mitochondrial unfolded protein response (UPR mt ). Indeed, the expression of key transcription factors that induce the UPR mt (ATF4, ATF5, and DDIT3) was increased following TMEM160 depletion. Expression of the mitochondrial protein import-receptors TOMM22 and TOMM20 was also enhanced. In addition, we observed a significant increase in reactive oxygen species (ROS) generation following TMEM160 depletion. Glutathione S-transferases, which detoxify the products of oxidative stress, were also upregulated in TMEM160-depleted cells. Immunoblot analysis was performed to detect proteins modified by 4-hydroxynonenal (which is released after the peroxidation of lipids by ROS): the expression patterns of 4-hydroxynonenalmodified proteins were altered after TMEM160 depletion, suggesting that depletion enhanced degradation of these proteins. HSPD1, TOMM22, ATF4, ATF5, and DDIT3 remained upregulated after ROS was scavenged by N-acetylcysteine, suggesting that once the UPR mt is induced by TMEM160 depletion, it is not suppressed by the subsequent detoxification of ROS. These findings suggest that TMEM160 may suppress ROS generation and stabilize mitochondrial protein(s).

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“…In summary, pterostilbene in combination with mitochondrial cofactors treatment activates SIRT3 and UPR mt as compensatory mechanisms as well as enhance sirtuins' levels and mitochondrial activity in several cell models of mitochondrial diseases. Recent findings have led to an increase in the relevance of UPR mt activation as a novel therapeutic approach for the treatment of mitochondrial diseases and related conditions (Poveda-Huertes et al, 2021) (Ji et al, 2020). Interestingly, this potent compensatory pathway may not be active in cells bearing a range of different mutations that secondarily affect mitochondrial proteostasis (Pitera et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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Increased mitochondrial protein import and cardiolipin remodelling upon early mtUPR

Cited by 23 publications

References 57 publications

ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle

ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle

Knockdown of TMEM160 leads to an increase in reactive oxygen species generation and the induction of the mitochondrial unfolded protein response

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

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