Loss of high‐temperature requirement protein A2 protease activity induces mitonuclear imbalance via differential regulation of mitochondrial biogenesis in sarcopenia

IUBMB Life ◽  
2020 ◽  
Vol 72 (8) ◽  
pp. 1659-1679
Author(s):  
Haohan Zhou ◽  
Danni Yuan ◽  
Weinan Gao ◽  
Jiayi Tian ◽  
Hongyu Sun ◽  
...  
Keyword(s):  
High Temperature ◽  
Mitochondrial Biogenesis ◽  
Protease Activity ◽  
Differential Regulation ◽  
Temperature Requirement

scholarly journals Loss of HtrA2/Omi protease activity induces mitonuclear imbalance and sarcopenia via differential regulation of mitochondrial biogenesis

2020 ◽  
Author(s):  
Haohan Zhou ◽  
Danni Yuan ◽  
Weinan Gao ◽  
Jiayi Tian ◽  
Hongyu Sun ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Protease Activity ◽  
Differential Regulation

Abstract The authors have withdrawn this preprint from Research Square

scholarly journals Loss of HtrA2/Omi protease activity induces mitonuclear imbalance and sarcopenia via differential regulation of mitochondrial biogenesis

2020 ◽  
Author(s):  
Haohan Zhou ◽  
Danni Yuan ◽  
Weinan Gao ◽  
Jiayi Tian ◽  
Hongyu Sun ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Protease Activity ◽  
Premature Death ◽  
Differential Regulation ◽  
Premature Aging ◽  
Expression Of Genes ◽  
Related Quality ◽  
Health Related ◽  
Ros Burst ◽  
Protease Deficient

Abstract Background Cellular homeostasis requires tight coordination between nucleus and mitochondria, organelles that each possess their own genomes. Disrupted mitonuclear communication has been found to be implicated in many aging processes. However little is known about mitonuclear signaling regulator in sarcopenia which is a major contributor to the risk of poor health-related quality of life, disability and premature death in older people. HtrA2/Omi is a mitochondrial protease and play an important role in mitochondrial proteostasis. HtrA2 mnd2(-/-) mice harboring protease-deficient HtrA2/Omi Ser276Cys missense mutants exhibit premature aging phenotype. Additionally, HtrA2/Omi has been established as a signaling regulator in nervous system and tumors. We therefore asked whether HtrA2/Omi participates in mitonuclear signaling regulation in aging muscle.Methods Using motor functional, histological and molecular biological methods, we characterized the muscle phenotype of HtrA2 mnd2(-/-) mice. We employed bioinformatics analysis and identified HtrA2/Omi as a gene differentially associated with nDNA/mtDNA gene expression in sarcopenia. Further, we isolated the gastrocnemius muscle of HtrA2 mnd2(-/-) mice and determined expression of genes in UPR mt , mitohormesis, electron transport chain (ETC), and mitochondrial biogenesis.Results Here, we showed that HtrA2/Omi protease deficiency induced denervation-independent skeletal muscle degeneration. Despite of mitochondrial hypofunction, upregulation of UPR mt and mitohormesis related genes and elevated reactive oxygen species (ROS) production were not observed in HtrA2 mnd2(-/-) mice, contrary to previous assumptions that loss of protease activity of HtrA2/Omi would lead to mitochondrial dysfunction as a result of proteostasis disturbance and ROS burst. Instead, we showed that HtrA2/Omi protease deficiency results in different changes between the expression of nDNA and mtDNA encoded ETC subunits, which is in consistent with their transcription factors NRF-1/2 and coactivator PGC-1α, suggesting that HtrA2/Omi protease activity may differentially regulate mitonuclear signaling via mitochondrial biogenesis in sarcopenia. Besides, Akt1 but not GSK3β showed increased expression level in HtrA2 mnd2(-/-) muscles, indicating an involvement of Akt1 in PGC-1α regulation response to HtrA2/Omi protease deficiency.Conclusions HtrA2/Omi protease deficiency induces mitonuclear imbalance and sarcopenia via differential regulation of mitochondrial biogenesis. The novel mechanistic insights may be of importance in developing new therapeutic strategies for sarcopenia.

scholarly journals The crystal structure of Mycobacterium tuberculosis high-temperature requirement A protein reveals an autoregulatory mechanism

2018 ◽  
Vol 74 (12) ◽  
pp. 803-809
Author(s):  
Arvind Kumar Gupta ◽  
Debashree Behera ◽  
Balasubramanian Gopal
Keyword(s):  
Crystal Structure ◽  
Mycobacterium Tuberculosis ◽  
High Temperature ◽  
Catalytic Domain ◽  
Pdz Domain ◽  
Regulatory Pathways ◽  
Inactive Conformation ◽  
Temperature Requirement ◽  
Autoregulatory Mechanism

The crystal structure of Mycobacterium tuberculosis high-temperature requirement A (HtrA) protein was determined at 1.83 Å resolution. This membrane-associated protease is essential for the survival of M. tuberculosis. The crystal structure reveals that interactions between the PDZ domain and the catalytic domain in HtrA lead to an inactive conformation. This finding is consistent with its proposed role as a regulatory protease that is conditionally activated upon appropriate environmental triggers. The structure provides a basis for directed studies to evaluate the role of this essential protein and the regulatory pathways that are influenced by this protease.

scholarly journals High-Temperature Requirement A1 (Htra1) - A Novel Regulator of Canonical Wnt Signaling

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Oriane Globus ◽  
Tamar Evron ◽  
Michal Caspi ◽  
Ronen Siman-Tov ◽  
Rina Rosin-Arbesfeld
Keyword(s):  
High Temperature ◽  
Wnt Signaling ◽  
Canonical Wnt Signaling ◽  
Temperature Requirement ◽  
Canonical Wnt

The crystal structure of an essential high-temperature requirement protein HtrA1 (Rv1223) from Mycobacterium tuberculosis reveals its unique features

2018 ◽  
Vol 74 (9) ◽  
pp. 906-921 ◽  
Author(s):  
Khundrakpam Herojit Singh ◽  
Savita Yadav ◽  
Deepak Kumar ◽  
Bichitra Kumar Biswal
Keyword(s):  
Crystal Structure ◽  
Amino Acids ◽  
Mycobacterium Tuberculosis ◽  
High Temperature ◽  
Protein Quality ◽  
Pdz Domain ◽  
Survival Strategies ◽  
Dimensional Structure ◽  
Protease Domain ◽  
Temperature Requirement

High-temperature requirement A (HtrA) proteins, which are members of the heat-shock-induced serine protease family, are involved in extracytoplasmic protein quality control and bacterial survival strategies under stress conditions, and are associated with the virulence of several pathogens; they are therefore major drug targets. Mycobacterium tuberculosis possesses three putative HtrAs: HtrA1 (Rv1223), HtrA2 (Rv0983) and HtrA3 (Rv0125). Each has a cytoplasmic region, a transmembrane helix and a periplasmic region. Here, the crystal structure of the periplasmic region consisting of a protease domain (PD) and a PDZ domain from an M. tuberculosis HtrA1 mutant (mHtrA1S387A) is reported at 2.7 Å resolution. Although the mHtrA1S387A PD shows structural features similar to those of other HtrAs, its loops, particularly L3 and LA, display different conformations. Loop L3 communicates between the PDs of the trimer and the PDZ domains and undergoes a transition from an active to an inactive conformation, as reported for an equivalent HtrA (DegS). Loop LA, which is responsible for higher oligomer formation owing to its length (50 amino acids) in DegP, is very short in mHtrA1S387A (five amino acids), as in mHtrA2 (also five amino acids), and therefore lacks essential interactions for the formation of higher oligomers. Notably, a well ordered loop known as the insertion clamp in the PDZ domain interacts with the protease domain of the adjacent molecule, which possibly aids in the stabilization of a trimeric functional unit of this enzyme. The three-dimensional structure of mHtrA1S387A presented here will be useful in the design of enzyme-specific antituberculosis inhibitors.

Behaviour of a high-temperature-requirement A (HtrA) deletion mutant of Brucella abortus in goats

1996 ◽  
Vol 60 (1) ◽  
pp. 48-50 ◽  
Author(s):  
P.H Elzer ◽  
S.D Hagius ◽  
G.T Robertson ◽  
R.W Phillips ◽  
J.V Walker ◽  
...  
Keyword(s):  
High Temperature ◽  
Brucella Abortus ◽  
Deletion Mutant ◽  
Temperature Requirement

Flowering responses to vernalization and photoperiod in annual medics (Medicago spp.)

1975 ◽  
Vol 26 (5) ◽  
pp. 831 ◽  
Author(s):  
NM Clarkson ◽  
JS Russell
Keyword(s):  
High Temperature ◽  
Flowering Time ◽  
Vernalization Requirement ◽  
Vernalization Response ◽  
The Third ◽  
Long Day ◽  
Temperature Requirement ◽  
New Finding ◽  
Annual Medics

The three processes thought to control flowering times in annual medics (Medicago spp.) are a vernalization requirement, a long day requirement and a high temperature requirement. To examine the first two processes, seed of seven cultivars of six species was vernalized at 1�C for periods of up to 11 weeks, then grown to flowering under three photoperiods in a glasshouse. To study the third process, the time to flowering of selected treatments from this expcrirnent was compared with flowering data from plants grown in the field at a range of temperatures lower than in the glasshouse. Vernalization and photoperiod caused large shifts in flowering time but the effects varied widely among species. M. scutellata was almost insensitive to both factors but in M. rugosa acceleration of up to 91 days was caused by treatment. Vernalization and short dark periods were additive in accelerating flowering and largely able to substitute for each other. Species flowered almost simultaneously when given their most favourable conditions for flowering. High temperature accelerated flowering in all species studied. However, in species other than M. scutellata it was necessary for a vernalization requirement to be met before this effect was observed. A new finding was that the vernalization response in M. truncatula and M. littoralis was largely reversed after more than 7 weeks of vernalization. This suggests a previously undetected flowering mechanism in these species.

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