Cardiomyocyte-specific loss of mitochondrial p32/C1qbp causes cardiomyopathy and activates stress responses

Saito, Toshiro; Uchiumi, Takeshi; Yagi, Minoru; Amamoto, Rie; Setoyama, Daiki; Matsushima, Yohkazu; Kang, Dongchon

doi:10.1093/cvr/cvx095

Cited by 48 publications

(56 citation statements)

References 39 publications

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“…One top-scoring YBEY partner was the putative RNA-binding protein p32/C1QBP, critically required for mitochondrial metabolism and associated with a variety of mitochondrial diseases and cancer (67)(68)(69)(70)(71)(72)(73)(74)(75)(76). The interaction between the two proteins was confirmed in cross-pulldown assays with the alternate use of YBEY-3×FLAG and p32-HA proteins as bait and prey (Supplementary Figure 8A).…”

Section: Ybey Interacts With P32 and A Distinct Set Of Mitoribosomal mentioning

confidence: 86%

YBEY is an essential biogenesis factor for mitochondrial ribosomes

Summer

Smirnova

Gabriele

et al. 2019

Preprint

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Ribosome biogenesis requires numerous trans-acting factors, some of which are deeply conserved. In Bacteria, the endoribonuclease YbeY is believed to be involved in 16S rRNA 3'-end processing and its loss was associated with ribosomal abnormalities. In Eukarya, YBEY appears to generally localize to mitochondria (or chloroplasts). Here we show that the deletion of human YBEY results in a severe respiratory deficiency and morphologically abnormal mitochondria as an apparent consequence of impaired mitochondrial translation. Reduced stability of 12S rRNA and the deficiency of several proteins of the small ribosomal subunit in YBEY knockout cells pointed towards a defect in mitochondrial ribosome biogenesis. The specific interaction of mitoribosomal protein uS11m with YBEY suggests that the latter recruits uS11m to the nascent small subunit in its late assembly stage. This scenario shows similarities with final stages of cytosolic ribosome biogenesis, and may represent a late checkpoint before the mitoribosome engages in translation. INTRODUCTIONRibosome biogenesis is a highly complex process that starts co-transcriptionally and includes ribosomal RNA processing, modification, and binding of ribosomal proteins (1). Each of these steps relies on specific factors, some of which are remarkably conserved. One such factor is the UPF0054 family protein YbeY found in all classified bacteria (2). Based on studies in various bacteria, YbeY has been implicated in ribosome maturation and quality control, with a particularly important role in small subunit (SSU) biogenesis (3-8), and post-transcriptional gene expression regulation (9-14). The deletion of ybeY is often lethal or associated with severe alterations of cellular metabolism and growth, indicating its indispensability for a wide variety of bacterial-type ribosomes (4,6,7,(13)(14)(15)(16)(17).Mechanistically, YbeY has been described as a metal-dependent endoribonuclease (5,12), and in some bacteria, ybeY mutants accumulate 16S rRNA with an unprocessed 3' end (3,5,7,8). Therefore, YbeY was proposed to be the "missing" 3' endoribonuclease required for 16S rRNA maturation to obtain the correct anti-Shine-Dalgarno sequence, which is needed for translation initiation on most bacterial mRNAs. However, this 16S rRNA 3'-misprocessing phenotype could equally be caused by the loss of a ribosome biogenesis factor that is not per se involved in rRNA cleavage (18), and so the precise role of YbeY in ribosome biogenesis remains unclear.By carrying out an in-depth phylogenetic analysis, we found that YBEY is also conserved in many eukaryal lineages, including animals, plants, most stramenopiles and alveolates (Supplementary Figure 1). Indeed, YbeY of Arabidopsis thaliana was reported to be an essential ribosome biogenesis factor in chloroplasts, and its absence was associated with severe misprocessing of nearly all chloroplast rRNAs, resulting in deficiency of organellar translation, and hence, the absence of photosynthesis (16). Human YBEY, which shares 27% of identity with YbeY of...

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Section: Ybey Interacts With P32 and A Distinct Set Of Mitoribosomal mentioning

confidence: 86%

YBEY is an essential biogenesis factor for mitochondrial ribosomes

Summer

Smirnova

Gabriele

et al. 2019

Preprint

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“…In summary, our study has identified the mitochondrial protein p32 as an important factor for metabolism and maturation in DCs. Recent studies on mice revealed that p32 is involved in cardiomyopathy (Saito et al, 2017), innate immunity (Sasaki et al, 2017), and obesity (Liu et al, 2017). Moreover, p32 mutations are associated with a clinical spectrum ranging from infantile lactic acidosis to childhood cardiomyopathy and late-onset progressive external ophthalmoplegia in humans (Feichtinger et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, using macrophages and mouse embryonic fibroblasts (MEFs), we demonstrated that p32 is required for appropriate interleukin (IL)-6 production upon lipopolysaccharide (LPS) stimulation (Sasaki et al, 2017). Recent studies showed that p32 mutations impair the mitochondrial respiratory chain and cause cardiomyopathy in humans and mice (Feichtinger et al, 2017;Saito et al, 2017). However, despite the importance of mitochondrial functions, the exact mechanisms of p32 functions in DCs remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial p32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation

et al. 2018

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“…Immunohistochemistry was conducted as described previously [18] with anti-von Willebrand Factor antibody (#65707; Cell Signaling Technology, Beverly, MA, U.S.A.).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Preserving the Endothelium in Saphenous Vein Graft with Both Conventional and No-Touch Preparation

Saito

Kurazumi

Suzuki

et al. 2020

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Background Despite the inferior patency compared to arterial grafts, a saphenous vein graft (SVG) is widely used for coronary artery bypass grafting (CABG). A lower atherosclerosis rate and higher patency have been reported for SVG obtained via the no-touch technique (NT) than via conventional preparation (CV). Although CV-mediated endothelial dysfunction is implied, the precise mechanism underlying the higher patency with NT is poorly understood. Methods Human residual SVGs during CABG and SVG sections after autopsy were analyzed. The endothelial surface was observed using scanning electron microscopy (SEM) and blindly compared between CV and NT. The endothelial integrity was also analyzed with immunohistochemistry.Results Unexpectedly, the hyperfine structure on SEM was comparable between CV and NT before grafting, and microvillus, a characteristic of endothelium, was indistinguishable between them. von Willebrand Factor, an endothelial marker, was equally detected throughout the vascular wall in both groups from residual and postmortem sections.Conclusions The morphological integrity of the endothelium was successfully preserved in SVG with CV, even at an ultrastructural level. Although its functionality remains to be addressed, other factors than the endothelium may be involved in the high patency obtained by NT. The present findings suggest that the characteristics of NT and surgical methodology should be reconsidered.

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Cardiomyocyte-specific loss of mitochondrial p32/C1qbp causes cardiomyopathy and activates stress responses

Abstract: These findings support a key role for mitochondrial p32 protein in cardiac myocytes modulating mitochondrial translation and function, and thereby survival.

Cited by 48 publications

References 39 publications

YBEY is an essential biogenesis factor for mitochondrial ribosomes

YBEY is an essential biogenesis factor for mitochondrial ribosomes

Mitochondrial p32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation

Preserving the Endothelium in Saphenous Vein Graft with Both Conventional and No-Touch Preparation

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