Deafness-associated mitochondrial 12S rRNA mutation reshapes mitochondrial and cellular homeostasis.

Human mitochondrial 12S ribosomal RNA (rRNA) 1555A>G mutation has been associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide. Our previous investigation revealed that the m.1555A>G mutation impaired mitochondrial translation and oxidative phosphorylation (OXPHOS).

Mutation of CRYAB encoding a conserved mitochondrial chaperone and antiapoptotic protein causes hereditary optic atrophy.

The degeneration of retinal ganglion cells (RGC) due to mitochondrial dysfunctions manifests optic neuropathy. However, the molecular components of RGC linked to optic neuropathy manifestations remain largely unknown. Here, we identified a potentially novel optic atrophy-causative CRYAB gene encoding a highly conserved major lens protein acting as mitochondrial chaperone and possessing antiapoptotic activities.

A homozygous mutation of TWNK identified in premature ovarian insufficiency warns of late-onset perrault syndrome.

Background: Primary ovarian insufficiency (POI) is defined as cessation of ovarian function before the age of 40 years, which is characterized by amenorrhoea, infertility, elevated gonadotrophin level and sex-steroid deficiency. The phenotypes of POI are heterogeneous, including isolated and syndromic forms. Perrault syndrome (PS), characterized by sensorineural hearing loss (SNHL) and ovarian dysfunction before 40 years in females, is one type of syndromic POI.

Clinical and genetic analysis of essential hypertension with mitochondrial tRNA 4435A>G and mutation.

Objectives: To investigate the role of m.4435A>G and c.572G>T (p.

Deafness-associated tRNA mutation impaired mitochondrial and cellular integrity.

Defects in mitochondrial RNA metabolism have been linked to sensorineural deafness that often occurs as a consequence of damaged or deficient inner ear hair cells. In this report, we investigated the molecular mechanism underlying a deafness-associated tRNA 593T > C mutation that changed a highly conserved uracil to cytosine at position 17 of the DHU-loop. The m.

Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis.

Mitochondria are dynamic organelles in cellular metabolism and physiology. Mitochondrial DNA (mtDNA) mutations are associated with a broad spectrum of clinical abnormalities. However, mechanisms underlying mtDNA mutations regulate intracellular signaling related to the mitochondrial and cellular integrity are less explored.

Induced pluripotent stem cells: ex vivo models for human diseases due to mitochondrial DNA mutations.

Mitochondria are essential organelles for cellular metabolism and physiology in eukaryotic cells. Human mitochondria have their own genome (mtDNA), which is maternally inherited with 37 genes, encoding 13 polypeptides for oxidative phosphorylation, and 22 tRNAs and 2 rRNAs for translation. mtDNA mutations are associated with a wide spectrum of degenerative and neuromuscular diseases.

Clinical and genetic analysis of essential hypertension with gene m.15024G>A mutation.

Objectives: To explore the role of mitochondrial 15024G>A mutation in the development of essential hypertension.

Methods: Mitochondrial genome sequences of hypertensive patients were obtained from previous studies. Clinical and genetic data of a hypertensive patient with mitochondrial 15024G>A mutation and its pedigree were analyzed.

cdh23 affects congenital hearing loss through regulating purine metabolism.

Introduction: The pathogenic gene plays a pivotal role in tip links, which is indispensable for mechanoelectrical transduction in the hair cells. However, the underlying molecular mechanism and signal regulatory networks that influence deafness is still largely unknown.

Methods: In this study, a congenital deafness family, whole exome sequencing revealed a new mutation in the pathogenic gene , subsequently; the mutation has been validated using Sanger sequencing method.

Optimized allotopic expression of mitochondrial ND6 transgene restored complex I and apoptosis deficiencies caused by LHON-linked ND6 14484T > C mutation.

Background: Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease due to mutations in mitochondrial DNA. However, there is no effective treatment for this disease. LHON-linked ND6 14484T > C (p.

Nuclear modifier YARS2 allele correction restored retinal ganglion cells-specific deficiencies in Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) is a maternally transmitted eye disease due to the degeneration of retinal ganglion cells (RGCs). Mitochondrial 11778G > A mutation is the most common LHON-associated mitochondrial DNA (mtDNA) mutation. Our recent studies demonstrated some LHON families manifested by synergic interaction between m.

Exportin 4 depletion leads to nuclear accumulation of a subset of circular RNAs.

Numerous RNAs are exported from the nucleus, abnormalities of which lead to cellular complications and diseases. How thousands of circular RNAs (circRNAs) are exported from the nucleus remains elusive. Here, we provide lines of evidence to demonstrate a link between the conserved Exportin 4 (XPO4) and nuclear export of a subset of circRNAs in metazoans.

Emerging functions of mitochondria-encoded noncoding RNAs.

Mitochondria, organelles that harbor their own circular genomes, are critical for energy production and homeostasis maintenance in eukaryotic cells. Recent studies discovered hundreds of mitochondria-encoded noncoding RNAs (mt-ncRNAs), including novel subtypes of mitochondria-encoded circular RNAs (mecciRNAs) and mitochondria-encoded double-stranded RNAs (mt-dsRNAs). Here, we discuss the emerging field of mt-ncRNAs by reviewing their expression patterns, biogenesis, metabolism, regulatory roles, and functional mechanisms.

A deafness-associated mitochondrial DNA mutation caused pleiotropic effects on DNA replication and tRNA metabolism.

In this report, we investigated the molecular mechanism underlying a deafness-associated m.5783C > T mutation that affects the canonical C50-G63 base-pairing of TΨC stem of tRNACys and immediately adjacent to 5' end of light-strand origin of mitochondrial DNA (mtDNA) replication (OriL). Two dimensional agarose gel electrophoresis revealed marked decreases in the replication intermediates including ascending arm of Y-fork arcs spanning OriL in the mutant cybrids bearing m.

Human TRUB1 is a highly conserved pseudouridine synthase responsible for the formation of Ψ55 in mitochondrial tRNAAsn, tRNAGln, tRNAGlu and tRNAPro.

Pseudouridine (Ψ) at position 55 in tRNAs plays an important role in their structure and function. This modification is catalyzed by TruB/Pus4/Cbf5 family of pseudouridine synthases in bacteria and yeast. However, the mechanism of TRUB family underlying the formation of Ψ55 in the mammalian tRNAs is largely unknown.

Abnormal morphology and function in retinal ganglion cells derived from patients-specific iPSCs generated from individuals with Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease that results from degeneration of retinal ganglion cells (RGC). Mitochondrial ND4 11778G > A mutation, which affects structural components of complex I, is the most prevalent LHON-associated mitochondrial DNA (mtDNA) mutation worldwide. The m.

Mitochondrial tRNA variants in 811 Chinese probands with Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) is the maternal inheritance of eye disorder. LHON-linked mitochondrial DNA (mtDNA) mutations affect the ND1, ND4 or ND6 genes encoding essential subunits of complex I. However, the role of mitochondrial tRNA defects in the pathogenesis of LHON is poorly understood.

Leber's hereditary optic neuropathy-associated ND6 14484T > C mutation caused pleiotropic effects on the complex I, RNA homeostasis, apoptosis and mitophagy.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease due to mitochondrial DNA (mtDNA) mutations. LHON-linked ND6 14484T > C (p.M64V) mutation affected structural components of complex I but its pathophysiology is poorly understood.

Mechanistic insights into multiple-step transport of mitochondrial ADP/ATP carrier.

The ADP/ATP carrier (AAC) is crucial for mitochondrial functions by importing ADP and exporting ATP across the inner mitochondrial membrane. However, the mechanism of highly specific ADP recognition and transport by AAC remains largely elusive. In this work, spontaneous ADP binding process to the ground c-state AAC was investigated through rigorous molecular dynamics simulations of over 31 microseconds in total.

Heteroplasmic and homoplasmic m.616T>C in mitochondria tRNAPhe promote isolated chronic kidney disease and hyperuricemia.

Inherited kidney diseases are the fifth most common cause of end-stage renal disease (ESRD). Mitochondrial dysfunction plays a vital role in the progression of inherited kidney diseases, while mitochondrial-transfer RNA (mt-tRNA) variants and their pathogenic contributions to kidney disease remain largely unclear. In this study, we identified the pathogenic mt-tRNAPhe 616T>C mutation in 3 families and documented that m.

Genetic correction of TRMU allele restored the mitochondrial dysfunction-induced deficiencies in iPSCs-derived hair cells of hearing-impaired patients.

Sensorineural hearing loss often results from damaged or deficient inner ear hair cells. Mitochondrial 12S rRNA 1555A>G mutation has been associated with hearing loss in many families. The m.

Verification of an iPSC line (LZUi002-A) from a patient with a novel mutation in the TBL1X gene.

More than 120 genes have been reported to be associated with deafness, and deletion of the TBL1X gene may cause deafness in humans. In this study, we generated an induced pluripotent stem cell (iPSC) line from dermal fibroblasts of a 34-year-old deaf person with a novel variant c.342_343insGCGGCG in the TBL1X gene.