Mitochondrial protein transport: Versatility of translocases and mechanisms

Busch, Jakob D.; Fielden, Laura F.; Pfanner, Nikolaus; Wiedemann, Nils

doi:10.1016/j.molcel.2023.02.020

Cited by 64 publications

(25 citation statements)

References 210 publications

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“…To assess mitochondrial protein import efficiency, we measured the import of the matrix protein ornithine transcarbamylase (OTC) in cells that stably express OTC-V5. The N-terminal mitochondrial targeting sequence (MTS) of OTC is cleaved upon import, allowing a separation of the un-imported precursor from the mature form of this protein by SDS-PAGE 4,32 . In untreated cells, the precursor of OTC-V5 was not detected due its efficient import and cleavage in the mitochondria ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…These proteins are translated as precursors with an N-terminal mitochondrial targeting sequence (MTS) that is cleaved by the mitochondrial processing peptidase (MPP) upon reaching the matrix. As protein import into the mitochondria often requires ATP and polarization of the inner mitochondrial membrane, it is susceptible to bioenergetic changes and various mitochondrial defects [4][5][6] . In addition, pathogenic mutations in protein import machinery genes, such as TIMM50 and acylglycerol kinase (AGK), directly affect delivery of proteins into the mitochondria [6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

“…Hence, the constant import of proteins into the mitochondria is essential for maintaining the function of these organelles. The vast majority of mitochondrial proteins are first inserted into the translocase of the outer membrane (TOM) and are subsequently targeted to mitochondrial sub-compartments through various mechanisms 4 . In the case of matrix proteins, the route into the mitochondria is through TOM and then the translocase of the inner membrane (TIM).…”

Section: Introductionmentioning

confidence: 99%

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ATAD1 and the integrated stress response prevent clogging of TOM and damage caused by un-imported mitochondrial proteins

Kim,

Goldstein,

Zecchel

et al. 2023

Preprint

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Mitochondria require the constant import of nuclear-encoded proteins for proper functioning. Impaired protein import not only depletes mitochondria of essential factors but also leads to toxic accumulation of un-imported proteins outside the organelle. Defects in mitochondrial protein import are associated with neurodegenerative and bioenergetic diseases. Here, we investigated the consequences of mitochondrial protein import stress in human cells. We demonstrated that un-imported proteins can clog the mitochondria by stalling inside the translocase of the outer membrane (TOM). We found that the integrated stress response (ISR) acted as the first line of defense to mitochondrial clogging by attenuating global protein translation and preventing excessive accumulation of un-imported proteins. A second mechanism, mediated by a mitochondrial ATPase, ATAD1, acted specifically to remove proteins from TOM and clear the entry gate into the mitochondria. ATAD1 interacted with both TOM and stalled proteins, and its knockout resulted in extensive accumulation of mitochondrial precursors as well as decreased protein import. Increased ATAD1 expression improved tolerance of cells to defective mitochondrial protein import, demonstrating the importance of this quality control pathway in surveilling protein import and its contribution to cellular health.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ATAD1 and the integrated stress response prevent clogging of TOM and damage caused by un-imported mitochondrial proteins

Kim,

Goldstein,

Zecchel

et al. 2023

Preprint

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“…In the subsequent years, numerous protein transport machineries have been identified as residents of most biological membranes; both general purpose and highly specific [4][5][6][7]. The most prevalent of these is the universal Sec systemthe protein translocation channel first postulated by Blobel.…”

Section: Introductionmentioning

confidence: 99%

A unifying mechanism for protein transport through the core bacterial Sec machinery

Allen,

Collinson

2023

Open Biol.

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Encapsulation and compartmentalization are fundamental to the evolution of cellular life, but they also pose a challenge: how to partition the molecules that perform biological functions—the proteins—across impermeable barriers into sub-cellular organelles, and to the outside. The solution lies in the evolution of specialized machines, translocons, found in every biological membrane, which act both as gate and gatekeeper across and into membrane bilayers. Understanding how these translocons operate at the molecular level has been a long-standing ambition of cell biology, and one that is approaching its denouement; particularly in the case of the ubiquitous Sec system. In this review, we highlight the fruits of recent game-changing technical innovations in structural biology, biophysics and biochemistry to present a largely complete mechanism for the bacterial version of the core Sec machinery. We discuss the merits of our model over alternative proposals and identify the remaining open questions. The template laid out by the study of the Sec system will be of immense value for probing the many other translocons found in diverse biological membranes, towards the ultimate goal of altering or impeding their functions for pharmaceutical or biotechnological purposes.

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“…Mitochondria are pivotal organelles of the eukaryotic cell that function in many processes, including oxidative phosphorylation, the b-oxidation of fatty acids, and the regulation of cell death. As the vast majority of mitochondrial genes moved to the nucleus during the process of evolution [1], the cell adapted by constructing specific translocation pathways [2][3][4][5]. Nuclear-encoded mitochondrial precursor proteins are translated on cytosolic ribosomes, and the targeting information they contain directs them into one of the four compartments within the organelle.…”

mentioning

confidence: 99%

Defective mitochondrial import as a challenge for cellular protein homeostasis

2023

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Mitochondria are organelles indispensable for the correct functioning of eukaryotic cells. Their significance for cellular homeostasis is manifested by the existence of complex quality control pathways that monitor organellar fitness. Mitochondrial biogenesis relies on the efficient import of mitochondrial precursor proteins, a large majority of which are encoded by nuclear DNA and synthesized in the cytosol. This creates a demand for highly specialized import routes that comprise cytosolic factors and organellar translocases. The passage of newly encoded mitochondrial precursor proteins through the cytosol to the translocase of the outer mitochondrial membrane (TOM) is under tight surveillance. As a result of mitochondrial import defects, mitochondrial precursor proteins accumulate in the cytosol or clog the TOM complex, which in turn stimulates cellular stress responses to minimize the consequences of these challenges. These responses are critical for maintaining protein homeostasis under conditions of mitochondrial stress. The present review summarizes recent advances in the field of mitochondrial protein import quality control and discusses the role of this quality control within the network of cellular mechanisms that maintain the cellular homeostasis of proteins.

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Mitochondrial protein transport: Versatility of translocases and mechanisms

Cited by 64 publications

References 210 publications

ATAD1 and the integrated stress response prevent clogging of TOM and damage caused by un-imported mitochondrial proteins

ATAD1 and the integrated stress response prevent clogging of TOM and damage caused by un-imported mitochondrial proteins

A unifying mechanism for protein transport through the core bacterial Sec machinery

Defective mitochondrial import as a challenge for cellular protein homeostasis

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