PERK-ATAD3A interaction protects mitochondrial proteins synthesis during ER stress

Hughes, Daniel T.; Brar, Karinder K; Morris, James B.; Subramanian, Kelly; Krishna, S. Sri; Gao, Fei; Rieder, Lara-Sophie; Freeman, Joshua L.; Smith, Heather; Jukes-Jones, Rebekkah; Nunnari, Jodi; Prudent, Julien; Butcher, Adrian J.; Mallucci, Giovanna R.

doi:10.1101/2022.07.24.501280

Cited by 4 publications

(3 citation statements)

References 26 publications

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“…One of these arms uses the ER-localized kinase PERK to phosphorylate eIF2a, which then attenuates cytoplasmic translation [ 158 ]. Hughes et al [ 160 ] now report that mitochondrial localized transcripts are exempt from the global translational repression due to a direct interaction between PERK and the OMM protein ATAD3a. How this affects the targeting of the encoded proteins has not been assessed.…”

Section: The Long (Or Short) Post-translational Journey To Mitochondriamentioning

confidence: 99%

The role of mitochondrial RNA association for mitochondrial homeostasis in neurons

Segura,

Harbauer

2024

Biochemical Journal

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The sub-compartmentalization of cellular processes is especially important in highly polarized cells such as neurons, as their function rely on their complex morphology. The association of RNAs to the mitochondrial surface is a conserved feature from yeast to humans and it regulates several aspects of mitochondrial physiology and, hence, cellular functions. In neurons, mitochondria are emerging as platforms for RNA transport and local protein translation. In this review, we discuss how RNA localization to mitochondria helps to sustain mitochondrial function, and how this can support mitochondrial homeostasis, especially in the distal parts of the neuron, to support neuronal activity.

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Section: The Long (Or Short) Post-translational Journey To Mitochondriamentioning

confidence: 99%

The role of mitochondrial RNA association for mitochondrial homeostasis in neurons

Segura,

Harbauer

2024

Biochemical Journal

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“…A recent preprint suggests that translational repression due to ER stress sensing is modulated at MERCS formed by a putative tether pair—ATPase Family AAA Domain Containing 3A (ATAD3A) at the mitochondria, and the ER stress-sensing kinase PERK on the other organelle. This contact allows the continued translation of mitochondrially localized ribosomes, despite global translational repression due to activation of the UPR [ 185 ]. It remains to be determined if these interacting proteins are a true, functional tether or if the interaction may be induced only downstream of RRBP1–SYNJ2BP tethering.…”

Section: Crosstalk Between Mitophagy and Mercsmentioning

confidence: 99%

Role of Mitochondria–ER Contact Sites in Mitophagy

Rühmkorf,

Harbauer

2023

Biomolecules

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Mitochondria are often referred to as the “powerhouse” of the cell. However, this organelle has many more functions than simply satisfying the cells’ metabolic needs. Mitochondria are involved in calcium homeostasis and lipid metabolism, and they also regulate apoptotic processes. Many of these functions require contact with the ER, which is mediated by several tether proteins located on the respective organellar surfaces, enabling the formation of mitochondria–ER contact sites (MERCS). Upon damage, mitochondria produce reactive oxygen species (ROS) that can harm the surrounding cell. To circumvent toxicity and to maintain a functional pool of healthy organelles, damaged and excess mitochondria can be targeted for degradation via mitophagy, a form of selective autophagy. Defects in mitochondria–ER tethers and the accumulation of damaged mitochondria are found in several neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis, which argues that the interplay between the two organelles is vital for neuronal health. This review provides an overview of the different mechanisms of mitochondrial quality control that are implicated with the different mitochondria–ER tether proteins, and also provides a novel perspective on how MERCS are involved in mediating mitophagy upon mitochondrial damage.

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“…ATAD3A and GRP78 together stabilize WASF3 at the mitochondrial membrane, promoting cancer metastasis [5,32]. Moreover, the N-terminus of ATAD3A directly interacts with the kinase insert loop of protein-kinase-R-like endoplasmic reticulum kinase (PERK), an ER stress senor kinase located in ER, attenuating the PERK-mediated signaling during ER stress (Figure 2 #5) [33].…”

Section: Atad3a-protein Interactions and Functionmentioning

confidence: 99%

ATAD3A: A Key Regulator of Mitochondria-Associated Diseases

Chen,

Li,

Zambidis

et al. 2023

IJMS

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Mitochondrial membrane protein ATAD3A is a member of the AAA-domain-containing ATPases superfamily. It is important for the maintenance of mitochondrial DNA, structure, and function. In recent years, an increasing number of ATAD3A mutations have been identified in patients with neurological symptoms. Many of these mutations disrupt mitochondrial structure, function, and dynamics and are lethal to patients at a young age. Here, we summarize the current understanding of the relationship between ATAD3A and mitochondria, including the interaction of ATAD3A with mitochondrial DNA and mitochondrial/ER proteins, the regulation of ATAD3A in cholesterol mitochondrial trafficking, and the effect of known ATAD3A mutations on mitochondrial function. In the current review, we revealed that the oligomerization and interaction of ATAD3A with other mitochondrial/ER proteins are vital for its various functions. Despite affecting different domains of the protein, nearly all documented mutations observed in ATAD3A exhibit either loss-of-function or dominant-negative effects, potentially leading to disruption in the dimerization of ATAD3A; autophagy; mitophagy; alteration in mitochondrial number, size, and cristae morphology; and diminished activity of mitochondrial respiratory chain complexes I, IV, and V. These findings imply that ATAD3A plays a critical role in mitochondrial dynamics, which can be readily perturbed by ATAD3A mutation variants.

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PERK-ATAD3A interaction protects mitochondrial proteins synthesis during ER stress

Cited by 4 publications

References 26 publications

The role of mitochondrial RNA association for mitochondrial homeostasis in neurons

The role of mitochondrial RNA association for mitochondrial homeostasis in neurons

Role of Mitochondria–ER Contact Sites in Mitophagy

ATAD3A: A Key Regulator of Mitochondria-Associated Diseases

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