Mitochondrial and Nuclear Accumulation of the Transcription Factor ATFS-1 Promotes OXPHOS Recovery during the UPRmt

Nargund, Amrita M.; Fiorese, Christopher J.; Pellegrino, Mark W.; Deng, Peng; Haynes, Cole M.

doi:10.1016/j.molcel.2015.02.008

Cited by 385 publications

(417 citation statements)

References 37 publications

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“…The control of mitochondrial function and UPR mt during stress in the worm is largely attributable to the activating transcription factor associated with stress, atfs-1 17,18 . Depletion of atfs-1 by RNAi feeding of the GMC101 worms, but not CL2122, caused a severe developmental delay even in absence of the “disease-inducing” temperature shift (Extended Data Fig.…”

Section: Mitochondrial Homeostasis Counters Aβ Proteotoxicitymentioning

confidence: 99%

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Sorrentino

Romani

Mouchiroud

et al. 2017

Nature

530

424

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Alzheimer’s disease (AD) is a common and devastating disease characterized by the aggregation of amyloid-β peptide (Aβ), yet we know relatively little about the underlying molecular mechanisms or how to treat AD patients. Here, we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in Aβ proteotoxic diseases in human, mouse and C. elegans, and which involves the UPRmt and mitophagy pathways. Using the worm model of Aβ proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed the induction of this mitochondrial stress response as key to maintain mitochondrial proteostasis and health. Importantly, boosting mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms, and in AD transgenic mice. Our data support the relevance of enhancing mitochondrial proteostasis to delay Aβ proteotoxic diseases, such as AD.

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Section: Mitochondrial Homeostasis Counters Aβ Proteotoxicitymentioning

confidence: 99%

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Sorrentino

Romani

Mouchiroud

et al. 2017

Nature

530

424

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“…How mitochondrial peptide extrusion affects the activity of the UPR mt is unclear, but it is clear that HAF-1 is not essential for UPR mt activation and instead serves as a modulator that impacts the nuclear accumulation of the bZIP transcription factor ATFS-1, a pivotal regulator of the UPR mt (7,10). ATFS-1 harbors two sorting signals able to target it to both mitochondria and the nucleus (7,11). Under physiological conditions, the MTS directs the localization of ATFS-1 to mitochondria where it is degraded by the protease Lon (7).…”

Section: Caenorhabditis Elegansmentioning

confidence: 99%

“…Paradoxically, in addition to nuclear accumulation, ATFS-1 also accumulates in mitochondria during stress despite reduced mitochondrial import efficiency (7,11). Multiple isoforms of ATFS-1 are present in mitochondria during the UPR mt , but the exact identity of these isoforms is still unknown.…”

Section: Metabolic Adaptationsmentioning

confidence: 99%

“…Multiple isoforms of ATFS-1 are present in mitochondria during the UPR mt , but the exact identity of these isoforms is still unknown. However, two splice variants of ATFS-1 exist with a difference of just 16 amino acids (11). Although both the short and long ATFS-1 isoforms contain the MTS, it is not known which isoform accumulates in mitochondria during stress.…”

Section: Metabolic Adaptationsmentioning

confidence: 99%

“…Although both the short and long ATFS-1 isoforms contain the MTS, it is not known which isoform accumulates in mitochondria during stress. Within mitochondria ATFS-1 binds the D-loop of mtDNA, an A-T-rich region residing in the control region adjacent to transcriptional regulatory elements (11). Here, ATFS-1 limits the abundance of OXPHOS transcripts encoded by the mitochondrial genome.…”

Section: Metabolic Adaptationsmentioning

confidence: 99%

See 2 more Smart Citations

The mitochondrial unfolded protein response: Signaling from the powerhouse

Qureshi

Haynes

Pellegrino

2017

Journal of Biological Chemistry

129

118

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Edited by Ruma BanerjeeMitochondria are multifaceted and indispensable organelles required for cell performance. Accordingly, dysfunction to mitochondria can result in cellular decline and possibly the onset of disease. Cells use a variety of means to recover mitochondria and restore homeostasis, including the activation of retrograde pathways such as the mitochondrial unfolded protein response (UPR mt ). In this Minireview, we will discuss how cells adapt to mitochondrial stress through UPR mt regulation. Furthermore, we will explore the current repertoire of biological functions that are associated with this essential stress-response pathway.Mitochondria are double membrane organelles commonly associated with the production of cellular energy via oxidative phosphorylation (OXPHOS).2 Mitochondria are also required for the metabolism of nucleotides, amino acids, and lipids and have an essential function in regulating apoptosis. Maintaining mitochondrial integrity is therefore a key aspect in ensuring cellular and organismal viability. Consequently, a decline in mitochondrial function is frequently associated with the development of numerous diseases (1).Mitochondria are dependent on a diverse compilation of proteins to carry out their vital functions. However, the mitochondrial proteome is faced with various challenges, most notably the partitioning of protein encoding genes between the mitochondrial and nuclear genomes. Remarkably, the human mitochondrial genome only encodes ϳ1% of the total mitochondrial proteome with the remaining proteins being encoded by nuclear genes (2). Sophisticated mechanisms have evolved to efficiently transfer nuclear-encoded mitochondrial proteins to their proper organelle destination following translation on cytosolic ribosomes. To accomplish this complex task, proteins are sorted to mitochondria via targeting sequences that form characteristic amphipathic helices composed of positively charged residues. Such mitochondrial targeting sequences (MTS) are recognized and translocated via the mitochondrial Tom-Tim complex to their respective sub-organelle compartment (3). Exquisite coordination of expression between the mitochondrial and nuclear genomes exists during mitochondrial biogenesis, as failure in genome coordination can disrupt the precise stoichiometry of these OXPHOS complexes resulting in orphan subunit accumulation and proteotoxicity (4). Further contributing to mitochondrial proteotoxicity is the possible damage to the mitochondrial genome from reactive oxygen species (ROS) produced by OXPHOS machinery as well as the ill effects of various environmental toxins. Mechanisms must therefore exist to ensure the protection of the mitochondrial proteome.Quality control of the mitochondrial proteome includes the functions of mitochondrial chaperones that assist in proper protein folding and proteases that promote clearance of misfolded proteins (5). Each sub-compartment of mitochondria houses its own quality control machinery to ensure protein homeostasis and organelle function. ...

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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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Mitochondrial and Nuclear Accumulation of the Transcription Factor ATFS-1 Promotes OXPHOS Recovery during the UPRmt

Cited by 385 publications

References 37 publications

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

The mitochondrial unfolded protein response: Signaling from the powerhouse

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

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