The NADH Dehydrogenase Nde1 Executes Cell Death after Integrating Signals from Metabolism and Proteostasis on the Mitochondrial Surface

Saladi, SreeDivya; Boos, Felix; Poglitsch, Michael; Meyer, Hadar; Sommer, Frederik; Mühlhaus, Timo; Schroda, Michael; Schuldiner, Maya; Madeo, Frank; Herrmann, Johannes M.

doi:10.1016/j.molcel.2019.09.027

Cited by 48 publications

(47 citation statements)

References 102 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A number of recent studies reported alternative approaches to follow the import reaction which resulted in surprising observations: (1) Ribosome profiling revealed that cytosolic chaperones and the signal recognition particle play crucial roles in distinguishing mitochondrial and secretory proteins already at very early steps in their synthesis (Schibich et al, 2016;Doring et al, 2017;Costa et al, 2018); (2) proximity labeling suggested that some mitochondrial proteins, in particular hydrophobic inner membrane proteins, explore the mitochondrial surface already during their synthesis (Jan et al, 2014;Williams et al, 2014; Vardi-Oknin and Arava, 2019; Wang et al, 2019) and that, in vivo, many (if not most) mitochondrial surface proteins are in direct proximity to the ER (Hung et al, 2017;Cho et al, 2020); (3) systematic screens of GFP-tagged protein libraries showed that many mitochondrial proteins are prone to accumulate in non-mitochondrial locations under certain growth conditions, in particular on the ER and within the nucleus (Vitali et al, 2018;Backes et al, 2020;Saladi et al, 2020;Shakya et al, 2020;Xiao et al, 2020) and, maybe even more surprising, observed non-mitochondrial residents in mitochondria (Ruan et al, 2017;Bader et al, 2020); and (4) genetic screens reported a very close cooperation of the mitochondrial and ER surface in protein biogenesis (Kornmann et al, 2009;Papic et al, 2013;Okreglak and Walter, 2014;Gamerdinger et al, 2015;Wohlever et al, 2017;Hansen et al, 2018;Vitali et al, 2018;Dederer et al, 2019;Matsumoto et al, 2019). Thus, in vivo, the surfaces of the ER and of mitochondria apparently vividly cooperate to sort proteins to the correct intracellular location.…”

Section: Discussionmentioning

confidence: 99%

“…Precursor proteins that accumulate in the cytosol can be highly toxic (Wang and Chen, 2015;Wrobel et al, 2015) and elicit response programs to counteract these deleterious consequences (Nargund et al, 2012;Weidberg and Amon, 2018;Boos et al, 2019;Song et al, 2020;Zöller et al, 2020). The stability of many precursor proteins in the cytosol is low thanks to surveillance of the ubiquitin/proteasome system for uninserted precursors (Bragoszewski et al, 2017;Kowalski et al, 2018;Paasch et al, 2018;Saladi et al, 2020;Shakya et al, 2020). The association of mitochondrial precursors to the ER surface can retard their degradation and facilitate their productive targeting to the TOM complex by a process referred to as ER-SURF (Hansen et al, 2018;Xiao et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The ER protein Ema19 facilitates the degradation of nonimported mitochondrial precursor proteins

Laborenz

Bykov

Knöringer

et al. 2021

MBoC

Self Cite

View full text Add to dashboard Cite

For the biogenesis of mitochondria, hundreds of proteins need to be targeted from the cytosol into the various compartments of this organelle. The intramitochondrial targeting routes these proteins take to reach their respective location in the organelle are well understood. However, the early targeting processes, from cytosolic ribosomes to the membrane of the organelle, are still largely unknown. In this study, we present evidence that an integral membrane protein of the endoplasmic reticulum (ER), Ema19, plays a role in this process. Mutants lacking Ema19 show an increased stability of mitochondrial precursor proteins, indicating that Ema19 promotes the proteolytic degradation of non-productive precursors. The deletion of Ema19 improves the growth of respiration-deficient cells, suggesting that Ema19-mediated degradation can compete with productive protein import into mitochondria. Ema19 is the yeast representative of a conserved protein family. The human Ema19 homolog is known as sigma 2 receptor or TMEM97. Though its molecular function is not known, previous studies suggested a role of the sigma 2 receptor as a quality control factor in the ER, compatible with our observations about Ema19. More globally, our data provide an additional demonstration of the important role of the ER in mitochondrial protein targeting.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The ER protein Ema19 facilitates the degradation of nonimported mitochondrial precursor proteins

Laborenz

Bykov

Knöringer

et al. 2021

MBoC

Self Cite

View full text Add to dashboard Cite

show abstract

“…The following methods were performed according to published methods: Isolation of mitochondria and oxygen consumption measurements (Saladi, Boos et al, 2020); analysis of mRNA levels by qRT-PCR (Zöller et al, 2020); preparation of semi-intact cells and their use for in vitro import experiments (Laborenz et al, 2019); pulse chase assay and alkylation for in vivo analysis of Mia40-mediated import (Peleh et al, 2016); the analysis of mitochondrial protein import using the Oxa1-Ura3 reporter assay (Hansen et al, 2018); growth and analysis of MIA40-expressing HEK293T cells (Fischer, Horn et al, 2013, Murschall, Gerhards et al, 2020).…”

Section: Methodsmentioning

confidence: 99%

Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol

Schlagowski

Knöringer

Morlot

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

The formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient material and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but the causalities remained unclear. We used yeast as model system to analyze the relevance of mitochondrial processes for the behavior of an aggregation-prone polyQ protein derived from human huntingtin. Induction of Q97-GFP rapidly leads to insoluble cytosolic aggregates and cell death. Although this aggregation impairs mitochondrial respiration only slightly, it interferes with efficient import of mitochondrial precursor proteins. Mutants in the import component Mia40 are hypersensitive to Q97-GFP. Even more surprisingly, Mia40 overexpression strongly suppresses the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the posttranslational import into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Owing to its rate-limiting role for mitochondrial protein import, Mia40 acts as a regulatory component in this competition. This role of Mia40 as dynamic regulator in mitochondrial biogenesis can apparently be exploited to stabilize cytosolic proteostasis.

show abstract

“…Under basal conditions, Cdc48/p97 targets numerous mitochondrial proapoptotic factors for degradation, preventing apoptosis [82,161]. Recently, such an antiapoptotic role of Cdc48 was described, involving the reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase protein Nde1, the yeast homologue of the mammalian apoptosis-inducing factor (AIF) [162]. Nde1 forms two distinct topomers, residing in the IMS, ensuring enzymatic activity, or instead located at the OMM and facing the cytosol, triggering cell death.…”

Section: Pro-and Antiapoptotic Roles Of Cdc48 In Mitochondriamentioning

confidence: 99%

Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion

Escobar-Henriques

Anton

2020

IJMS

View full text Add to dashboard Cite

Cdc48/p97 is a ring-shaped, ATP-driven hexameric motor, essential for cellular viability. It specifically unfolds and extracts ubiquitylated proteins from membranes or protein complexes, mostly targeting them for proteolytic degradation by the proteasome. Cdc48/p97 is involved in a multitude of cellular processes, reaching from cell cycle regulation to signal transduction, also participating in growth or death decisions. The role of Cdc48/p97 in endoplasmic reticulum-associated degradation (ERAD), where it extracts proteins targeted for degradation from the ER membrane, has been extensively described. Here, we present the roles of Cdc48/p97 in mitochondrial regulation. We discuss mitochondrial quality control surveillance by Cdc48/p97 in mitochondrial-associated degradation (MAD), highlighting the potential pathologic significance thereof. Furthermore, we present the current knowledge of how Cdc48/p97 regulates mitofusin activity in outer membrane fusion and how this may impact on neurodegeneration.

show abstract

The NADH Dehydrogenase Nde1 Executes Cell Death after Integrating Signals from Metabolism and Proteostasis on the Mitochondrial Surface

Cited by 48 publications

References 102 publications

The ER protein Ema19 facilitates the degradation of nonimported mitochondrial precursor proteins

The ER protein Ema19 facilitates the degradation of nonimported mitochondrial precursor proteins

Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol

Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion

Contact Info

Product

Resources

About