Pathways to balance mitochondrial translation and protein import

Priesnitz, Chantal; Becker, Thomas

doi:10.1101/gad.316547.118

Cited by 90 publications

(68 citation statements)

References 128 publications

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“…The mitochondrial translation comprises the same four stages, although mitochondria have their own translation machinery with distinct mitochondrial ribosomes (mitoribosome), tRNAs and translation factors than the cytosolic counterparts. Yet the majority of the mitochondrial proteins, including all factors required for mtDNA maintenance and expression, and some components of the ETC complexes are encoded in the nuclear genome (96) and are translated in cytosolic ribosomes, and transported into mitochondria via peptides that function as import signals, this mitochondrial proteins are widely regulated via mTORC1 (97). Since mTORC1 regulates the cellular most energy consuming process, it is reasonable that mTORC1 responds to bioenergetics variation, a process controlled by mitochondria.…”

Section: Mtorc1 Regulates Translation Of Mitochondrial Proteins Encodmentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients. de la Cruz López et al. mTORC1 and Mitochondrial Functions Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a shared affiliation, though no other collaboration, with with several of the authors AG and KC.

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Section: Mtorc1 Regulates Translation Of Mitochondrial Proteins Encodmentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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“…A spectacu-lar example illustrating the importance and immediate functional consequences of local protein biosynthesis is given by neurons where efficient protein production in distal axons is required to control synaptic transmission (73,74). Similarly, the importance of localized translation in the production of proteins that constitute the major organelles is generally well established (58,69). Interestingly, while the translation of ER-destined proteins is almost completely separated from the production of cytosolic proteins, substantial overlap exists between the protein biosynthesis and quality control pathways for mitochondrial and cytoplasmic proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, while this tRNA modification is normally pervasive and applied to most corresponding cytoplasmic tRNAs (60), it may be less present in cases of localized translation known to facilitate the synthesis of proteins destined to the major organelles. Of note, mitochondrial proteins often fold in the cytosol and their export to the mitochondria often share components of the cytoplasmic protein quality control network (69)(70)(71), in S.cerevisiae for instance the Hsp70 chaperone SSA1 (72). In contrast, translocation to the ER is directly coupled to translation as ER-destined proteins usually cannot fold inside the cytoplasm.…”

Section: Dt Sequences Link To Protein and Organelle Biogenesismentioning

confidence: 99%

Inferring translational heterogeneity from ribosome profiling data

Bordignon

Pechmann

2019

Preprint

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Translation of messenger RNAs into proteins by the ribosome is the most important step of protein biosynthesis. Accordingly, translation is tightly controlled and heavily regulated to maintain cellular homeostasis. Ribosome profiling (Ribo-seq) has revolutionized the study of translation by revealing many of its underlying mechanisms. However, equally many aspects of translation remain mysterious, in part also due to persisting challenges in the interpretation of data obtained from Ribo-seq experiments. Here, we show that some of the variability observed in Ribo-seq data has biological origins and reflects programmed heterogeneity of translation. To systematically identify sequences that are differentially translated (DT) across mRNAs beyond what can be attributed to experimental variability, we performed a comparative analysis of Ribo-seq data from Saccharomyces cerevisiae and derived a consensus ribosome density profile that reflects consistent signals in individual experiments. Remarkably, the thus identified DT sequences link to mechanisms known to regulate translation elongation and are enriched in genes important for protein and organelle biosynthesis. Our results thus highlight examples of translational heterogeneity that are encoded in the genomic sequences and tuned to optimizing cellular homeostasis. More generally, our work highlights the power of Ribo-seq to understand the complexities of translation regulation.

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“…In addition, once proteins have reached their destination, compartment-specific mechanisms of protein quality control locally protect the proteome. Upon mitochondrial stress, several proteostasis networks have been nicely shown to operate at damaged mitochondria, for example to protect cells from death signals (D' Amico et al, 2017;Priesnitz and Becker, 2018).…”

Section: Mitochondrial Protein Quality Controlmentioning

confidence: 99%

Interplay between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis

Escobar-Henriques¹,

Altin²,

Brave³

2020

Current Issues in Molecular Biology

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Eukaryotic cells are subdivided into membranebound compartments specialized in different cellular functions and requiring dedicated sets of proteins. Although cells developed compartmentspecific mechanisms for protein quality control, chaperones and ubiquitin are generally required for maintaining cellular proteostasis. Proteotoxic stress is signalled from one compartment into another to adjust the cellular stress response. Moreover, transport of misfolded proteins between different compartments can buffer local defects in protein quality control. Mitochondria are special organelles in that they possess an own expression, folding and proteolytic machinery, of bacterial origin, which do not have ubiquitin. Nevertheless, the importance of extensive crosstalk between mitochondria and other subcellular compartments is increasingly clear. Here, we will present local quality control mechanisms and discuss how cellular proteostasis is affected by the interplay between mitochondria and the ubiquitin proteasome system.

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Pathways to balance mitochondrial translation and protein import

Cited by 90 publications

References 128 publications

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

Inferring translational heterogeneity from ribosome profiling data

Interplay between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis

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