Mitochondrial Kinases and the Role of Mitochondrial Protein Phosphorylation in Health and Disease

Kotrasová, Veronika; Keresztesová, Barbora; Ondrovičová, Gabriela; Bauer, Jacob; Havalová, Henrieta; Pevala, Vladimír; Kutějová, Eva; Kunová, Nina

doi:10.3390/life11020082

Cited by 20 publications

(14 citation statements)

References 382 publications

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“…Phosphorylation is a key regulatory element in mitochondria. Disturbances of phosphorylation patterns in mitochondria are closely connected to several disease phenotypes, including diabetes, cancer, and neurodegeneration (reviewed in [95]). Whether phosphorylation of mitochondrial-targeted proteins occurs before or after mitochondrial import, which kinases are involved respectively and how they are potentially imported into mitochondria still needs to be clarified.…”

Section: Post-translational Modifications (Ptms) and Their Role In The Assembly Processmentioning

confidence: 99%

Human Mitoribosome Biogenesis and Its Emerging Links to Disease

Sanchez

Krüger

Shiriaev

et al. 2021

IJMS

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Mammalian mitochondrial ribosomes (mitoribosomes) synthesize a small subset of proteins, which are essential components of the oxidative phosphorylation machinery. Therefore, their function is of fundamental importance to cellular metabolism. The assembly of mitoribosomes is a complex process that progresses through numerous maturation and protein-binding events coordinated by the actions of several assembly factors. Dysregulation of mitoribosome production is increasingly recognized as a contributor to metabolic and neurodegenerative diseases. In recent years, mutations in multiple components of the mitoribosome assembly machinery have been associated with a range of human pathologies, highlighting their importance to cell function and health. Here, we provide a review of our current understanding of mitoribosome biogenesis, highlighting the key factors involved in this process and the growing number of mutations in genes encoding mitoribosomal RNAs, proteins, and assembly factors that lead to human disease.

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Section: Post-translational Modifications (Ptms) and Their Role In The Assembly Processmentioning

confidence: 99%

Human Mitoribosome Biogenesis and Its Emerging Links to Disease

Sanchez

Krüger

Shiriaev

et al. 2021

IJMS

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“…There are a variety of functional consequences of phosphorylation and dephosphorylation of mitochondrial proteins, including their location, proper metabolism, the functionality of the Krebs cycle and OXPHOS, signalling, processes of fission and fusion, as well as the decision for mitophagy and apoptosis, reviewed in [ 62 , 63 ]. In this work, a substantial number of phosphorylation sites (besides the largest group of identified phosphosites among proteins with unknown function) was found within the OXPHOS components, particularly complexes III (subunits 6 and 8, heme and Rieske proteins), IV (subunits 4 and 5) and V (subunits 4, gamma, OSCP and beta) ( Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

Chronic Activation of AMPK Induces Mitochondrial Biogenesis through Differential Phosphorylation and Abundance of Mitochondrial Proteins in Dictyostelium discoideum

Heidorn-Czarna

Heidorn

Fernando

et al. 2021

IJMS

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Mitochondrial biogenesis is a highly controlled process that depends on diverse signalling pathways responding to cellular and environmental signals. AMP-activated protein kinase (AMPK) is a critical metabolic enzyme that acts at a central control point in cellular energy homeostasis. Numerous studies have revealed the crucial roles of AMPK in the regulation of mitochondrial biogenesis; however, molecular mechanisms underlying this process are still largely unknown. Previously, we have shown that, in cellular slime mould Dictyostelium discoideum, the overexpression of the catalytic α subunit of AMPK led to enhanced mitochondrial biogenesis, which was accompanied by reduced cell growth and aberrant development. Here, we applied mass spectrometry-based proteomics of Dictyostelium mitochondria to determine the impact of chronically active AMPKα on the phosphorylation state and abundance of mitochondrial proteins and to identify potential protein targets leading to the biogenesis of mitochondria. Our results demonstrate that enhanced mitochondrial biogenesis is associated with variations in the phosphorylation levels and abundance of proteins related to energy metabolism, protein synthesis, transport, inner membrane biogenesis, and cellular signalling. The observed changes are accompanied by elevated mitochondrial respiratory activity in the AMPK overexpression strain. Our work is the first study reporting on the global phosphoproteome profiling of D. discoideum mitochondria and its changes as a response to constitutively active AMPK. We also propose an interplay between the AMPK and mTORC1 signalling pathways in controlling the cellular growth and biogenesis of mitochondria in Dictyostelium as a model organism.

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“…In mitochondria, they have been shown to be involved in energy production, apoptosis, metabolism, and tissue response to ischemic injury [ 216 ]. The enzymes that modify mitochondrial proteins include the kinases and phosphatases responsible for phosphorylation and dephosphorylation events (review in [ 217 ]), an O -GlcNAc transferase responsible for O -GlcNAcylation, and SIRT5 (sirtuin-5), which acts in deacylations (desuccinylation, deglutarylation); some other occur non-enzymatically [ 216 ]. In mouse mitochondria, S -nitrosylation by the endothelial nitric oxide synthase (eNOS) found to be a common modification of proteins in the heart, brain, kidney, liver, lung, and thymus, which suggests that S -nitrosocystein-containing proteins are heavily used in metabolically active tissues [ 218 ].…”

Section: Mortalin Mortalin Co-chaperones Post-translational Modifications and Human Diseasesmentioning

confidence: 99%

Mitochondrial HSP70 Chaperone System—The Influence of Post-Translational Modifications and Involvement in Human Diseases

Havalová¹,

Ondrovičová²,

Keresztesová³

et al. 2021

IJMS

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Since their discovery, heat shock proteins (HSPs) have been identified in all domains of life, which demonstrates their importance and conserved functional role in maintaining protein homeostasis. Mitochondria possess several members of the major HSP sub-families that perform essential tasks for keeping the organelle in a fully functional and healthy state. In humans, the mitochondrial HSP70 chaperone system comprises a central molecular chaperone, mtHSP70 or mortalin (HSPA9), which is actively involved in stabilizing and importing nuclear gene products and in refolding mitochondrial precursor proteins, and three co-chaperones (HSP70-escort protein 1—HEP1, tumorous imaginal disc protein 1—TID-1, and Gro-P like protein E—GRPE), which regulate and accelerate its protein folding functions. In this review, we summarize the roles of mitochondrial molecular chaperones with particular focus on the human mtHsp70 and its co-chaperones, whose deregulated expression, mutations, and post-translational modifications are often considered to be the main cause of neurological disorders, genetic diseases, and malignant growth.

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Mitochondrial Kinases and the Role of Mitochondrial Protein Phosphorylation in Health and Disease

Cited by 20 publications

References 382 publications

Human Mitoribosome Biogenesis and Its Emerging Links to Disease

Human Mitoribosome Biogenesis and Its Emerging Links to Disease

Chronic Activation of AMPK Induces Mitochondrial Biogenesis through Differential Phosphorylation and Abundance of Mitochondrial Proteins in Dictyostelium discoideum

Mitochondrial HSP70 Chaperone System—The Influence of Post-Translational Modifications and Involvement in Human Diseases

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