The Unfolded Protein Response: At the Intersection between Endoplasmic Reticulum Function and Mitochondrial Bioenergetics

Carreras-Sureda, Amado; Pihán, Philippe; Hetz, Claudio

doi:10.3389/fonc.2017.00055

Cited by 40 publications

(33 citation statements)

References 63 publications

(75 reference statements)

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“…) and carry out important protein quality control activities such as the mitochondrial unfolded protein response (Carreras‐Sureda et al . ). Mitochondria are also an important site for production of reactive oxygen species important for signalling beneficial adaptations (Gonzalez‐Freire et al .…”

Section: Introductionmentioning

confidence: 97%

Mitochondrial proteostasis as a shared characteristic of slowed aging: the importance of considering cell proliferation

Hamilton

Miller

2017

The Journal of Physiology

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Incomplete conclusion that mitochondrial protein synthesis rate is slower in the long-lived model Protein synthesis Protein synthesis ≥ Insightful conclusion that new mitochondrial proteins synthesized are allocated to maintaining/ replacing proteins in existing cells in the long-lived model Simultaneously measure mitochondrial protein synthesis and DNA Synthesis rate Protein synthesis Protein synthesis ≥ DNA synthesis DNA synthesis < Control mouse Long-lived mouse Measure mitochondrial protein synthesis rate only Control mouse Long-lived mouseAbstract Proteostasis is one of the seven "pillars of aging research" identified by the Trans-NIH Geroscience Initiative and loss of proteostasis is associated with aging and age-related chronic disease. Accumulated protein damage and resultant cellular dysfunction are consequences of limited protein repair systems and slowed protein turnover. When relatively high rates of protein turnover are maintained despite advancing age, damaged proteins are more quickly degraded and replaced, maintaining proteome fidelity. Therefore, maintenance of protein turnover represents an important proteostatic mechanism. However, measurement of protein synthesis without consideration for cell proliferation can result in an incomplete picture, devoid of information about how new proteins are being allocated. Simultaneous measurement of protein and DNA synthesis provides necessary mechanistic insight about proteins apportioned for newly proliferating cells versus for somatic maintenance. Using this approach with a number of murine models of slowed aging shows that, compared to controls, energetic resources are directed more toward somatic maintenance and proteostasis, and away from cell growth and proliferation. In particular, slowed aging models are associated with heightened mechanisms of mitochondrial proteostatic maintenance. Taking cell proliferation into account may explain the paradoxical findings that aging itself and slowed aging interventions can both be characterized by slower rates of protein synthesis. Abstract figure legendProteostasis is one of the seven 'pillars of ageing research' identified by the Trans-NIH Geroscience Initiative, and loss of proteostasis is associated with ageing and age-related chronic disease. Maintenance of protein turnover represents an important mechanism for preserving proteome fidelity. However, measurement of protein synthesis without consideration for cell proliferation can result in an incomplete picture, devoid of information about how new proteins are being allocated. Simultaneous measurement of protein and DNA synthesis provides critical insight about proteins apportioned for newly proliferating cells versus for somatic maintenance. Using this approach with murine models of slowed ageing shows that mitochondrial proteostatic maintenance is a characteristic shared among these slowed ageing models.

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Section: Introductionmentioning

confidence: 97%

Mitochondrial proteostasis as a shared characteristic of slowed aging: the importance of considering cell proliferation

Hamilton

Miller

2017

The Journal of Physiology

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“…More recent studies have implicated specific mitochondrial-ER tethering proteins, such as FUNDC1, as having important roles in maintaining normal cardiac contractility in mice (64)(65)(66). Studies outside the cardiac context have shown that there are numerous components of the UPR ER that are associated with MAM structure and function, including ER chaperones, the IP 3 receptor and PERK, which, if deleted decreases calcium movement from the ER to mitochondria (67). Relatedly, PERK deletion in the heart disrupts calcium signaling in cardiac myocytes in mice, in vivo (68).…”

Section: Integrating Er and Mitochondrial Function In Cardiac Myocytesmentioning

confidence: 99%

Integrating ER and Mitochondrial Proteostasis in the Healthy and Diseased Heart

Arrieta

Blackwood

Stauffer

et al. 2020

Front. Cardiovasc. Med.

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The integrity of the proteome in cardiac myocytes is critical for robust heart function. Proteome integrity in all cells is managed by protein homeostasis or proteostasis, which encompasses processes that maintain the balance of protein synthesis, folding, and degradation in ways that allow cells to adapt to conditions that present a potential challenge to viability (1). While there are processes in various cellular locations in cardiac myocytes that contribute to proteostasis, those in the cytosol, mitochondria and endoplasmic reticulum (ER) have dominant roles in maintaining cardiac contractile function. Cytosolic proteostasis has been reviewed elsewhere (2, 3); accordingly, this review focuses on proteostasis in the ER and mitochondria, and how they might influence each other and, thus, impact heart function in the settings of cardiac physiology and disease.

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“…Given that MFN2 is present on the ER membrane, it also regulates ER-mitochondria tethering (de Brito and Scorrano, 2008). This connection, known as ER mitochondria-associated membranes (MAMs), has been shown to play an essential role in the regulation of ER, mitochondrial, and cellular functions (Ngoh et al, 2012;Hamasaki et al, 2013;Schneeberger et al, 2013;Muñoz et al, 2014;Carreras-Sureda et al, 2017;Pathak and Trebak, 2018). MFN2 downregulation is associated with decreased expression of subunits of the Krebs cycle and electron transport chain, reduced oxygen consumption, lower DY m , and increased reactive oxygen species (ROS) (Santel and Fuller, 2001;Yasukawa et al, 2009;Ngoh et al, 2012;Wakai et al, 2014;Filadi et al, 2015;Schrepfer and Scorrano, 2016).…”

Section: Basic Aspects Of Mitochondriamentioning

confidence: 99%

“…These are linked with buffering of Ca +2 levels, innate immunity, apoptosis and biogenesis of iron-sulfur clusters (Yasukawa et al, 2009;Naon and Scorrano 2014;Stehling et al, 2014). Moreover, mitochondria closely interact with other organelles such as the endoplasmic reticulum (ER) and regulate several pathways in the cell (de Brito and Scorrano, 2009;Betz et al, 2013;Chen et al, 2014;Carreras-Sureda et al, 2017;Xu et al, 2017). As a result, perturbations in mitochondrial function may dramatically disturb cellular homeostasis, resulting in several common diseases in humans (Bach et al, 2003;Chen et al, 2007Chen et al, , 2010Schaefer et al, 2008;Misko et al, 2012;Schon et al, 2012;Sebastian et al, 2012;Eschbach et al, 2013;Payne et al, 2013;Schneeberger et al, 2013;Pareyson et al, 2015;Ramírez et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Maternal transmission of mitochondrial diseases

et al. 2020

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Given the major role of the mitochondrion in cellular homeostasis, dysfunctions of this organelle may lead to several common diseases in humans. Among these, maternal diseases linked to mitochondrial DNA (mtDNA) mutations are of special interest due to the unclear pattern of mitochondrial inheritance. Multiple copies of mtDNA are present in a cell, each encoding for 37 genes essential for mitochondrial function. In cases of mtDNA mutations, mitochondrial malfunctioning relies on mutation load, as mutant and wild-type molecules may co-exist within the cell. Since the mutation load associated with disease manifestation varies for different mutations and tissues, it is hard to predict the progeny phenotype based on mutation load in the progenitor. In addition, poorly understood mechanisms act in the female germline to prevent the accumulation of deleterious mtDNA in the following generations. In this review, we outline basic aspects of mitochondrial inheritance in mammals and how they may lead to maternally-inherited diseases. Furthermore, we discuss potential therapeutic strategies for these diseases, which may be used in the future to prevent their transmission.

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The Unfolded Protein Response: At the Intersection between Endoplasmic Reticulum Function and Mitochondrial Bioenergetics

Cited by 40 publications

References 63 publications

Mitochondrial proteostasis as a shared characteristic of slowed aging: the importance of considering cell proliferation

Mitochondrial proteostasis as a shared characteristic of slowed aging: the importance of considering cell proliferation

Integrating ER and Mitochondrial Proteostasis in the Healthy and Diseased Heart

Maternal transmission of mitochondrial diseases

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