Methionine Sulfoxide Reductase B3-Targeted<i>In Utero</i>Gene Therapy Rescues Hearing Function in a Mouse Model of Congenital Sensorineural Hearing Loss

Kim, Mina; Cho, Hyun-Ju; Bae, Sanghyuk; Lee, Byeonghyeon; Oh, Se‐Kyung; Kwon, Tae-Jun; Ryoo, Zae-Young; Kim, Hwa-Young; Cho, Jin‐Ho; Kim, Un-Kyung; Lee, Kyu-Yup

doi:10.1089/ars.2015.6442

Cited by 64 publications

(52 citation statements)

References 55 publications

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“…Reduced MsrA and MsrB correlate with senile hair graying (Wood et al , ), epidermal damage (Schallreuter et al , ), and vitiligo (Zhou et al , ). Msr have also been implicated with neurodegenerative diseases such as Alzheimer's and Parkinson's disease (Glaser et al , ), auditory function and hearing loss (Kwon et al , ; Kim et al , ), visual deterioration (Pascual et al , ), and obesity (Styskal et al , ), and insulin resistance (Kaneto et al , ). As we have highlighted, mutation of Met192 (M192L and M192V) is recognized to be associated with Parkinson's disease (Foroud et al , ), the same site as the MetO, and its reduction by MsrB2.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial MsrB2 serves as a switch and transducer for mitophagy

Lee

et al. 2019

EMBO Mol Med

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Mitophagy can selectively remove damaged toxic mitochondria, protecting a cell from apoptosis. The molecular spatial–temporal mechanisms governing autophagosomal selection of reactive oxygen species (ROS)‐damaged mitochondria, particularly in a platelet (no genomic DNA for transcriptional regulation), remain unclear. We now report that the mitochondrial matrix protein MsrB2 plays an important role in switching on mitophagy by reducing Parkin methionine oxidation (MetO), and transducing mitophagy through ubiquitination by Parkin and interacting with LC3. This biochemical signaling only occurs at damaged mitochondria where MsrB2 is released from the mitochondrial matrix. MsrB2 platelet‐specific knockout and in vivo peptide inhibition of the MsrB2/LC3 interaction lead to reduced mitophagy and increased platelet apoptosis. Pathophysiological importance is highlighted in human subjects, where increased MsrB2 expression in diabetes mellitus leads to increased platelet mitophagy, and in platelets from Parkinson's disease patients, where reduced MsrB2 expression is associated with reduced mitophagy. Moreover, Parkin mutations at Met192 are associated with Parkinson's disease, highlighting the structural sensitivity at the Met192 position. Release of the enzyme MsrB2 from damaged mitochondria, initiating autophagosome formation, represents a novel regulatory mechanism for oxidative stress‐induced mitophagy.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial MsrB2 serves as a switch and transducer for mitophagy

Lee

et al. 2019

EMBO Mol Med

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“…used in utero rAAV2/1- MsrB3 (methionine sulfoxide reductase B3) to rescue MsrB3 −/− mice and showed hearing deterioration after 4 weeks. 30 …”

Section: Discussionmentioning

confidence: 99%

RNA Interference Prevents Autosomal-Dominant Hearing Loss

Shibata

Ranum

Moteki

et al. 2016

The American Journal of Human Genetics

102

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Hearing impairment is the most common sensory deficit. It is frequently caused by the expression of an allele carrying a single dominant missense mutation. Herein, we show that a single intracochlear injection of an artificial microRNA carried in a viral vector can slow progression of hearing loss for up to 35 weeks in the Beethoven mouse, a murine model of non-syndromic human deafness caused by a dominant gain-of-function mutation in Tmc1 (transmembrane channel-like 1). This outcome is noteworthy because it demonstrates the feasibility of RNA-interference-mediated suppression of an endogenous deafness-causing allele to slow progression of hearing loss. Given that most autosomal-dominant non-syndromic hearing loss in humans is caused by this mechanism of action, microRNA-based therapeutics might be broadly applicable as a therapy for this type of deafness.

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“…Likewise, dominant de novo mutations of MICALs substrate residues on actin, the Met‐44 and Met‐47 residues, have been characterized in both skeletal muscle and smooth muscle actins in human patients and they lead to actin accumulation defects that resemble the effects of mutating MICALs, as well as muscular dystrophies and vasculature disorders [Hoffjan et al, ; Hung et al, ; Laing et al, ; Regalado et al, ]. Furthermore, disruptions to the SelR/MsrB enzymes that reverse MICAL‐mediated effects on actin dynamics have also been linked to neurodegenerative disorders, aging processes, and deafness (e.g., [Ahmed et al, ; Kim and Gladyshev ; Kim et al, ]). It is also possible that MICALs may have other direct substrates besides F‐actin (i.e., proteins that activate the NADPH consumption activity of MICAL and are directly targeted by MICAL) — but in any case, it is interesing to consider that MICALs may also have indirect substrates based on their ability to release oxidants such as H 2 O 2 during the course of their enzyme reaction [reviewed in Hung and Terman ].…”

Section: Mical Flavoprotein Monooxygenases: F‐actin Effects and Cellumentioning

confidence: 99%

“…Likewise, dominant de novo mutations of MICALs substrate residues on actin, the Met-44 and Met-47 residues, have been characterized in both skeletal muscle and smooth muscle actins in human patients and they lead to actin accumulation defects that resemble the effects of mutating MICALs, as well as muscular dystrophies and vasculature disorders [Hoffjan et al, 2011;Hung et al, 2010b;Laing et al, 2009;Regalado et al, 2014]. Furthermore, disruptions to the SelR/MsrB enzymes that reverse MICAL-mediated effects on actin dynamics have also been linked to neurodegenerative disorders, aging processes, and deafness (e.g., [Ahmed et al, 2011;Kim and Gladyshev 2007;Kim et al, 2016]). It is also possible that MICALs may have other direct substrates Fig.…”

Section: Mical Flavoprotein Monooxygenases: F-actin Effects and Cellumentioning

confidence: 99%

Actin filaments—A target for redox regulation

et al. 2016

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Actin and its ability to polymerize into dynamic filaments is critical for the form and function of cells throughout the body. While multiple proteins have been characterized as affecting actin dynamics through non-covalent means, actin and its protein regulators are also susceptible to covalent modifications of their amino acid residues. In this regard, oxidation-reduction (Redox) intermediates have emerged as key modulators of the actin cytoskeleton with multiple different effects on cellular form and function. Here, we review work implicating Redox intermediates in post-translationally altering actin and discuss what is known regarding how these alterations affect the properties of actin. We also focus on two of the best characterized enzymatic sources of these Redox intermediates – the NADPH oxidase NOX and the flavoprotein monooxygenase MICAL – and detail how they have both been identified as altering actin, but share little similarity and employ different means to regulate actin dynamics. Finally, we discuss the role of these enzymes and redox signaling in regulating the actin cytoskeleton in vivo and highlight their importance for neuronal form and function in health and disease.

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Methionine Sulfoxide Reductase B3-TargetedIn UteroGene Therapy Rescues Hearing Function in a Mouse Model of Congenital Sensorineural Hearing Loss

Abstract: Our results provide insight into the role of MsrB3 in hearing function and bring us one step closer to hearing restoration as a fundamental therapy.

Cited by 64 publications

References 55 publications

Mitochondrial MsrB2 serves as a switch and transducer for mitophagy

Mitochondrial MsrB2 serves as a switch and transducer for mitophagy

RNA Interference Prevents Autosomal-Dominant Hearing Loss

Actin filaments—A target for redox regulation

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