The MyMOMA domain of MYO19 encodes for distinct Miro‐dependent and Miro‐independent mechanisms of interaction with mitochondrial membranes

Bocanegra, Jennifer L.; Fujita, Buntaro; Melton, Natalie R.; Cowan, James M.; Schinski, Elizabeth L.; Tamir, Tigist Y.; Major, Michael B.; Quintero, Omar A.

doi:10.1002/cm.21560

Cited by 27 publications

(37 citation statements)

References 115 publications

(230 reference statements)

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“…While stable subplasmalemmal actin rings form periodic structures that wrap around axons to support the axonal membrane, dynamic intra-axonal filaments help to enrich actin at presynaptic terminals (Ganguly et al, 2015;Xu, Zhong, & Zhuang, 2013). It has been reported that mitochondrial receptors Miro1/2 regulate recruitment and stability of myosin-19, thus likely coordinating MT-and actin-based mitochondrial trafficking in mouse embryonic fibroblasts (MEFs) (Bocanegra et al, 2020;López-Doménech et al, 2018;Oeding et al, 2018;Quintero et al, 2009). However, the role of myosin-19 in axonal mitochondrial trafficking is not clear.…”

Section: Regulation Of Axonal Mitochondrial Motilit Ymentioning

confidence: 99%

Developmental regulation of microtubule‐based trafficking and anchoring of axonal mitochondria in health and diseases

Cheng

Sheng

2020

Developmental Neurobiology

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Mitochondria are cellular power plants that supply most of the ATP required in the brain to power neuronal growth, function, and regeneration. Given their extremely polarized structures and extended long axons, neurons face an exceptional challenge to maintain energy homeostasis in distal axons, synapses, and growth cones.Anchored mitochondria serve as local energy sources; therefore, the regulation of mitochondrial trafficking and anchoring ensures that these metabolically active areas are adequately supplied with ATP. Chronic mitochondrial dysfunction is a hallmark feature of major aging-related neurodegenerative diseases, and thus, anchored mitochondria in aging neurons need to be removed when they become dysfunctional.Investigations into the regulation of microtubule (MT)-based trafficking and anchoring of axonal mitochondria under physiological and pathological circumstances represent an important emerging area. In this short review article, we provide an updated overview of recent in vitro and in vivo studies showing (1) how mitochondria are transported and positioned in axons and synapses during neuronal developmental and maturation stages, and (2) how altered mitochondrial motility and axonal energy deficits in aging nervous systems link to neurodegeneration and regeneration in a disease or injury setting. We also highlight a major role of syntaphilin as a key MTbased regulator of axonal mitochondrial trafficking and anchoring in mature neurons.

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Section: Regulation Of Axonal Mitochondrial Motilit Ymentioning

confidence: 99%

Developmental regulation of microtubule‐based trafficking and anchoring of axonal mitochondria in health and diseases

Cheng

Sheng

2020

Developmental Neurobiology

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“…The three IQ-motifs bind regulatory light chains (RLCs) of non-muscle and smooth muscle myosin 2 ( Lu et al, 2014 ). The relatively short tail region (146 aa in human Myo19) is unique and responsible for binding to mitochondria through an interaction with lipids ( Hawthorne et al, 2016 ; Shneyer et al, 2016 ) and Miro ( López-Doménech et al, 2018 ; Oeding et al, 2018 ; Bocanegra et al, 2020 ). Interestingly, the dissociation of Myo19 from Miro leads to its degradation ( López-Doménech et al, 2018 ; Oeding et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Coordination of mitochondrial and cellular dynamics by the actin-based motor Myo19

Majstrowicz¹,

Honnert²,

Nikolaus³

et al. 2021

Journal of Cell Science

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Myosin XIX (Myo19) is an actin-based motor that competes with adaptors of microtubule-based motors for binding to the outer mitochondrial transmembrane proteins Miro1 and Miro2 (collectively Miro, also known as RhoT1 and RhoT2, respectively). Here, we investigate which mitochondrial and cellular processes depend on the coordination of Myo19 and microtubule-based motor activities. To this end, we created Myo19-deficient HEK293T cells. Mitochondria in these cells were not properly fragmented at mitosis and were partitioned asymmetrically to daughter cells. Respiratory functions of mitochondria were impaired and ROS generation was enhanced. On a cellular level, cell proliferation, cytokinesis and cell–matrix adhesion were negatively affected. On a molecular level, Myo19 regulates focal adhesions in interphase, and mitochondrial fusion and mitochondrially associated levels of fission protein Drp1 and adaptor proteins dynactin and TRAK1 at prometaphase. These alterations were due to a disturbed coordination of Myo19 and microtubule-based motor activities by Miro.

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“…This assumption is supported by the fact that Ahnak1 is an interaction partner of myosin XIX (MYO19) that is associated with the mitochondrial outer membrane. 61 , 62 , 63 Our results showed that Ahnak1 is localized on the mitochondrial membrane, most likely at the outer mitochondrial membrane, and thus serves as a novel mitochondrial‐associated‐membrane protein. Based on the data obtained in this study, we assume that Ahnak1 binds to the contact sites on the mitochondrial membrane required for mitochondrial fusion, possibly masking these sites, which could disturb the mitochondrial fusion process.…”

Section: Discussionmentioning

confidence: 67%

Age‐related decline in murine heart and skeletal muscle performance is attenuated by reduced Ahnak1 expression

Mahmoodzadeh

Koch

Schriever

et al. 2021

J cachexia sarcopenia muscle

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Background Aging is associated with a progressive reduction in cellular function leading to poor health and loss of physical performance. Mitochondrial dysfunction is one of the hallmarks of aging; hence, interventions targeting mitochondrial dysfunction have the potential to provide preventive and therapeutic benefits to elderly individuals. Meta-analyses of age-related gene expression profiles showed that the expression of Ahnak1, a protein regulating several signal-transduction pathways including metabolic homeostasis, is increased with age, which is associated with low VO 2MAX and poor muscle fitness. However, the role of Ahnak1 in the aging process remained unknown. Here, we investigated the age-related role of Ahnak1 in murine exercise capacity, mitochondrial function, and contractile function of cardiac and skeletal muscles. Methods We employed 15-to 16-month-old female and male Ahnak1-knockout (Ahnak1-KO) and wild-type (WT) mice and performed morphometric, biochemical, and bioenergetics assays to evaluate the effects of Ahnak1 on exercise capacity and mitochondrial morphology and function in cardiomyocytes and tibialis anterior (TA) muscle. A human left ventricular (LV) cardiomyocyte cell line (AC16) was used to investigate the direct role of Ahnak1 in cardiomyocytes. ResultsWe found that the level of Ahnak1 protein is significantly up-regulated with age in the murine LV (1.9-fold) and TA (1.8-fold) tissues. The suppression of Ahnak1 was associated with improved exercise tolerance, as all aged adult Ahnak1-KO mice (100%) successfully completed the running programme, whereas approximately 31% male and 8% female WT mice could maintain the required running speed and distance. Transmission electron microscopic studies showed that LV and TA tissue specimens of aged adult Ahnak1-KO of both sexes have significantly more enlarged/elongated mitochondria and less small mitochondria compared with WT littermates (P < 0.01 and P < 0.001, respectively) at basal level. Further, we observed a shift in mitochondrial fission/fusion balance towards fusion in cardiomyocytes and TA muscle from aged adult Ahnak1-KO mice. The maximal and reserve respiratory capacities were significantly higher in cardiomyocytes from aged adult Ahnak1-KO mice compared with the WT counterparts (P < 0.05 and P < 0.01, respectively). Cardiomyocyte contractility and fatigue resistance of TA muscles were significantly increased in Ahnak1-KO mice of both sexes, compared with the WT groups. In vitro studies using AC16 cells have confirmed that the alteration of mitochondrial function is indeed a direct effect of Ahnak1. Finally, we presented Ahnak1 as a novel cardiac mitochondrial membrane-associated protein.Conclusions Our data suggest that Ahnak1 is involved in age-related cardiac and skeletal muscle dysfunction and could therefore serve as a promising therapeutical target.

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The MyMOMA domain of MYO19 encodes for distinct Miro‐dependent and Miro‐independent mechanisms of interaction with mitochondrial membranes

Cited by 27 publications

References 115 publications

Developmental regulation of microtubule‐based trafficking and anchoring of axonal mitochondria in health and diseases

Developmental regulation of microtubule‐based trafficking and anchoring of axonal mitochondria in health and diseases

Coordination of mitochondrial and cellular dynamics by the actin-based motor Myo19

Age‐related decline in murine heart and skeletal muscle performance is attenuated by reduced Ahnak1 expression

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