scholarly journals Mitochondrial functional resilience after TFAM ablation in adult cardiomyocytes

2020 ◽  
Author(s):  
Nasab Ghazal ◽  
Jessica N. Peoples ◽  
Tahmina Mohuiddin ◽  
Jennifer Q. Kwong
Keyword(s):  
Respiratory Chain ◽  
Energy Supply ◽  
Nuclear Genome ◽  
Transcript Abundance ◽  
Mitochondrial Translation ◽  
Adult Heart ◽  
Protein Levels ◽  
Mitochondrial Transcription Factor ◽  
Adult Cardiomyocytes ◽  
Mtdna Transcription

AbstractThe adult heart is a terminally differentiated tissue that depends on mitochondria for its energy supply. Respiratory chain energy supply deficits due to alterations in the mitochondrial genome (mtDNA) or in nuclear genome (nDNA)-encoded mtDNA regulators are associated with cardiac pathologies ranging from primary mitochondrial cardiomyopathies to heart failure. Mitochondrial transcription factor A (TFAM) is an nDNA-encoded regulator of mtDNA transcription, replication, and maintenance. Insufficiency of this protein in embryonic and postnatal cardiomyocytes causes cardiomyopathy and/or lethality, establishing TFAM as indispensable to the developing heart; its role in adult tissue has been inferred from these findings. Here, we provide evidence that challenges this long-standing paradigm using Tfam ablation in the adult heart. Unexpectedly, loss of Tfam in adult cardiomyocytes resulted in a prolonged period of functional resilience characterized by preserved mtDNA content, mitochondrial function, and cardiac function despite mitochondrial structural alterations and decreased transcript abundance. Remarkably, TFAM protein levels did not directly dictate mtDNA content in the adult heart, and mitochondrial translation was preserved with acute TFAM inactivation, suggesting a mechanism whereby respiratory chain assembly and function can be sustained, which we term ‘functional resilience’. Finally, long-term Tfam inactivation induced a coordinated downregulation of the core mtDNA transcription and replication machinery that ultimately resulted in mitochondrial dysfunction and cardiomyopathy. Taken together, adult-onset cardiomyocyte-specific Tfam inactivation reveals a striking resilience of the adult heart to acute insults to mtDNA regulatory mechanisms and provides insight into critical differences between the developing versus differentiated heart.

scholarly journals Mitochondrial functional resilience after TFAM ablation in the adult heart

2021 ◽  
Author(s):  
Nasab Ghazal ◽  
Jessica N. Peoples ◽  
Tahmina A. Mohiuddin ◽  
Jennifer Q. Kwong
Keyword(s):  
Nuclear Genome ◽  
Transcript Abundance ◽  
Mitochondrial Translation ◽  
Adult Heart ◽  
Protein Levels ◽  
Developing Heart ◽  
Mtdna Transcription ◽  
Transcription And Replication

The nuclear genome-encoded mitochondrial DNA (mtDNA) transcription factor A (TFAM) is indispensable for mitochondrial energy production in the developing and postnatal heart; a similar role for TFAM is inferred in adult heart. Here, we provide evidence that challenges this long-standing paradigm. Unexpectedly, conditionalTfam ablation in vivo in adult mouse cardiomyocytes resulted in a prolonged period of functional resilience characterized by preserved mtDNA content, mitochondrial function, and cardiac function, despite mitochondrial structural alterations and decreased transcript abundance. Remarkably, TFAM protein levels did not directly dictate mtDNA content in the adult heart, and mitochondrial translation was preserved with acute TFAM inactivation, suggesting maintenance of respiratory chain assembly/function. Long-term Tfam inactivation, however, downregulated the core mtDNA transcription and replication machinery, leading to mitochondrial dysfunction and cardiomyopathy. Collectively, in contrast to the developing heart, these data reveal a striking resilience of the differentiated adult heart to acute insults to mtDNA regulation.

scholarly journals Nuclear genome-wide associations with mitochondrial heteroplasmy

2021 ◽  
Vol 7 (12) ◽  
pp. eabe7520
Author(s):  
Priyanka Nandakumar ◽  
Chao Tian ◽  
Jared O’Connell ◽  
David Hinds ◽  
Andrew D. Paterson ◽  
...  
Keyword(s):  
Nuclear Genome ◽  
Multiple Roles ◽  
European Ancestry ◽  
Mitochondrial Transcription Factor ◽  
Genome Wide ◽  
Mtdna Sequence ◽  
Nuclear Component ◽  
Mitochondrial Transcription Factor A ◽  
Mitochondrial Heteroplasmy ◽  
The Stability

The role of the nuclear genome in maintaining the stability of the mitochondrial genome (mtDNA) is incompletely known. mtDNA sequence variants can exist in a state of heteroplasmy, which denotes the coexistence of organellar genomes with different sequences. Heteroplasmic variants that impair mitochondrial capacity cause disease, and the state of heteroplasmy itself is deleterious. However, mitochondrial heteroplasmy may provide an intermediate state in the emergence of novel mitochondrial haplogroups. We used genome-wide genotyping data from 982,072 European ancestry individuals to evaluate variation in mitochondrial heteroplasmy and to identify the regions of the nuclear genome that affect it. Age, sex, and mitochondrial haplogroup were associated with the extent of heteroplasmy. GWAS identified 20 loci for heteroplasmy that exceeded genome-wide significance. This included a region overlapping mitochondrial transcription factor A (TFAM), which has multiple roles in mtDNA packaging, replication, and transcription. These results show that mitochondrial heteroplasmy has a heritable nuclear component.

Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes

1992 ◽  
Vol 12 (2) ◽  
pp. 480-490
Author(s):  
M P King ◽  
Y Koga ◽  
M Davidson ◽  
E A Schon
Keyword(s):  
Steady State ◽  
Lactic Acidosis ◽  
Respiratory Chain ◽  
Mitochondrial Myopathy ◽  
Polyacrylamide Gel Electrophoresis ◽  
Mitochondrial Protein ◽  
Morphological Characteristics ◽  
Nucleotide Position ◽  
Mitochondrial Translation ◽  
Steady State Levels

Cytoplasts from two unrelated patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) harboring an A----G transition at nucleotide position 3243 in the tRNA(Leu(UUR)) gene of the mitochondrial genome were fused with human cells lacking endogenous mitochondrial DNA (mtDNA) (rho 0 cells). Selected cybrid lines, containing less than 15 or greater than or equal to 95% mutated genomes, were examined for differences in genetic, biochemical, and morphological characteristics. Cybrids containing greater than or equal to 95% mutant mtDNA, but not those containing normal mtDNA, exhibited decreases in the rates of synthesis and in the steady-state levels of the mitochondrial translation products. In addition, NADH dehydrogenase subunit 1 (ND 1) exhibited a slightly altered mobility on polyacrylamide gel electrophoresis. The mutation also correlated with a severe respiratory chain deficiency. A small but consistent increase in the steady-state levels of an RNA transcript corresponding to 16S rRNA + tRNA(Leu(UUR)) + ND 1 genes was detected. However, there was no evidence of major errors in processing of the heavy-strand-encoded transcripts or of altered steady-state levels or ratios of mitochondrial rRNAs or mRNAs. These results provide evidence for a direct relationship between the tRNALeu(UUR) mutation and the pathogenesis of this mitochondrial disease.

scholarly journals Detecting respiratory chain deficiency in osteoblasts of older patients

2021 ◽  
Author(s):  
Daniel Hipps ◽  
Philip Dobson ◽  
Charlotte Warren ◽  
David McDonald ◽  
Andrew Fuller ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mouse Model ◽  
Respiratory Chain ◽  
Nuclear Genome ◽  
Mitochondrial Dna Mutation ◽  
Human Osteoblasts ◽  
Dna Mutation ◽  
Respiratory Chain Deficiency ◽  
Age Related ◽  
Cellular Dysfunction

Mitochondria contain their own genome which encodes 13 essential mitochondrial proteins and accumulates somatic variants at up to 10 times the rate of the nuclear genome. These mitochondrial genome variants lead to respiratory chain deficiency and cellular dysfunction. Work with the PolgAmut/PolgAmut mouse model, which has a high mitochondrial DNA mutation rate, showed enhanced levels of age related osteoporosis in affected mice along with respiratory chain deficiency in osteoblasts. To explore whether respiratory chain deficiency is also seen in human osteoblasts with age, we developed a protocol and analysis framework for imaging mass cytometry (IMC) in bone tissue sections to analyse osteoblasts in situ. We have demonstrated significant increases in complex I deficiency with age in human osteoblasts. This work is consistent with findings from the PolgAmut/PolgAmut mouse model and suggests that respiratory chain deficiency, as a consequence of the accumulation of age related mitochondrial DNA mutations, may have a significant role to play in the pathogenesis of human age related osteoporosis.

scholarly journals Upregulation of VEGF-A Without Angiogenesis in a Mouse Model of Dilated Cardiomyopathy Caused by Mitochondrial Dysfunction

2002 ◽  
Vol 50 (7) ◽  
pp. 935-944 ◽  
Author(s):  
Emma Tham ◽  
Jianming Wang ◽  
Fredrik Piehl ◽  
Günther Weber
Keyword(s):  
Transcription Factor ◽  
Dilated Cardiomyopathy ◽  
Capillary Density ◽  
Vascular Endothelial ◽  
Protein Levels ◽  
Mitochondrial Transcription Factor ◽  
Mitochondrial Transcription Factor A ◽  
Respiratory Chain Activity ◽  
Endothelial Growth Factor

Angiogenesis is implicated in a variety of human pathologies and may also play a role in the progression of heart failure. We have studied the expression of members of the vascular endothelial growth factor (VEGF) and the angiopoietin families and their receptors in mice lacking the mitochondrial transcription factor A. These mice lack functional respiratory chain activity in their myocytes and develop dilated cardiomyopathy (DCM) postnatally. We studied the hearts of the knockout mice by in situ hybridization, Western blotting analysis, and immunohistochemistry. VEGF-A mRNA and protein levels were elevated in the myocardium of the knockouts. Levels of the hypoxia inducible transcription factor 1 alpha (HIF1α) and of glyceraldehyde-3-phosphate dehydrogenase transcripts were also increased, whereas those of angiopoietin−1 and −2 were reduced. Despite the striking upregulation of VEGF-A, there was no increase in capillary density in the knockout hearts. This study suggests that a disturbance in angiogenesis may contribute to the pathogenesis of DCM.

scholarly journals Mrpl36 Is Important for Generation of Assembly Competent Proteins during Mitochondrial Translation

2009 ◽  
Vol 20 (10) ◽  
pp. 2615-2625 ◽  
Author(s):  
Martin Prestele ◽  
Frank Vogel ◽  
Andreas S. Reichert ◽  
Johannes M. Herrmann ◽  
Martin Ott
Keyword(s):  
Protein Synthesis ◽  
Respiratory Chain ◽  
Large Subunit ◽  
Critical Role ◽  
Mitochondrial Translation ◽  
Respiratory Chain Complexes ◽  
Ribosomal Subunits ◽  
Terminal Domain ◽  
Chain Complexes ◽  
Mitochondrial Ribosome

The complexes of the respiratory chain represent mosaics of nuclear and mitochondrially encoded components. The processes by which synthesis and assembly of the various subunits are coordinated remain largely elusive. During evolution, many proteins of the mitochondrial ribosome acquired additional domains pointing at specific properties or functions of the translation machinery in mitochondria. Here, we analyzed the function of Mrpl36, a protein associated with the large subunit of the mitochondrial ribosome. This protein, homologous to the ribosomal protein L31 from bacteria, contains a mitochondria-specific C-terminal domain that is not required for protein synthesis per se; however, its absence decreases stability of Mrpl36. Cells lacking this C-terminal domain can still synthesize proteins, but these translation products fail to be properly assembled into respiratory chain complexes and are rapidly degraded. Surprisingly, overexpression of Mrpl36 seems to even increase the efficiency of mitochondrial translation. Our data suggest that Mrpl36 plays a critical role during translation that determines the rate of respiratory chain assembly. This important function seems to be carried out by a stabilizing activity of Mrpl36 on the interaction between large and small ribosomal subunits, which could influence accuracy of protein synthesis.

Role of D-type cyclins in heart development and disease

2012 ◽  
Vol 90 (9) ◽  
pp. 1197-1207 ◽  
Author(s):  
Adam Hotchkiss ◽  
Jessica Robinson ◽  
Jessica MacLean ◽  
Tiam Feridooni ◽  
Karim Wafa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Heart Development ◽  
Cardiac Development ◽  
Perinatal Period ◽  
Cell Cycle Regulators ◽  
Adult Heart ◽  
Signalling Molecules ◽  
Adult Cardiomyocytes ◽  
Catalytically Active ◽  
Permanent Cell

A defining feature of embryonic cardiomyocytes is their relatively high rates of proliferation. A gradual reduction in proliferative capacity throughout development culminates in permanent cell cycle exit by the vast majority of cardiomyocytes around the perinatal period. Accordingly, the adult heart has severely limited capacity for regeneration in response to injury or disease. The D-type cyclins (cyclin D1, D2, and D3) along with their catalytically active partners, the cyclin dependent kinases, are positive cell cycle regulators that play important roles in regulating proliferation of cardiomyocytes during normal heart development. While expression of D-type cyclins is generally low in the adult heart, expression levels are augmented in association with cardiac hypertrophy, but are uncoupled from myocyte cell division. Accordingly, re-activation of D-type cyclin expression in the adult heart has been implicated in pathophysiological processes via mechanisms distinct from those that drive proliferation during cardiac development. Growth factors and other exogenous agents regulate D-type cyclin production and activity in embryonic and adult cardiomyocytes. Understanding differences in the precise intracellular mediators downstream from these signalling molecules in embryonic versus adult cardiomyocytes could prove valuable for designing strategies to reactivate the cell cycle in cardiomyocytes in the setting of cardiovascular disease in the adult heart.

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