Mitochondrial Populations Exhibit Differential Dynamic Responses to Increased Energy Demand during Exocytosis In Vivo

Porat-Shliom, Natalie; Harding, Olivia J.; Malec, Lenka; Narayan, Kedar; Weigert, Roberto

doi:10.1016/j.isci.2018.12.036

Cited by 32 publications

(22 citation statements)

References 36 publications

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“…It is generally well accepted that dividing cells, including cancer cells, meet their energy demands by reprogramming their cell metabolism such as altering mitochondrial dynamics. 37,38 Our data suggested that MCU-mediated mitochondrial Ca 2+ uptake may promote mitochondrial fission and inhibit mitochondrial fusion, which is in agreement with several previous reports. 20,21 Over the past decades, multiple studies have reported that mitochondrial biogenesis and quality control are often upregulated in various types of cancer, including breast cancer, lung cancer, and hepatocellular carcinoma.…”

Section: Discussionsupporting

confidence: 93%

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MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

Yang

Jin

Wang

et al. 2020

Sig Transduct Target Ther

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Mitochondrial calcium uniporter (MCU) has an important role in regulating mitochondrial calcium (Ca 2+) homeostasis. Dysregulation of mitochondrial Ca 2+ homeostasis has been implicated in various cancers. However, it remains unclear whether MCU regulates mitochondrial Ca 2+ uptake to promote cell growth in colorectal cancer (CRC). Therefore, in the present study the expression of MCU in CRC tissues and its clinical significance were examined. Following which, the biological function of MCUmediated mitochondrial Ca 2+ uptake in CRC cell growth and the underlying mechanisms were systematically evaluated using in in vitro and in vivo assays, which included western blotting, cell viability and apoptosis assays, as well as xenograft nude mice models. Our results demonstrated that MCU was markedly upregulated in CRC tissues at both the mRNA and protein levels. Upregulated MCU was associated with poor prognosis in patients with CRC. Our data reported that upregulation of MCU enhanced the mitochondrial Ca 2+ uptake to promote mitochondrial biogenesis, which in turn facilitated CRC cell growth in vitro and in vivo. In terms of the underlying mechanism, it was identified that MCU-mediated mitochondrial Ca 2+ uptake inhibited the phosphorylation of transcription factor A, mitochondrial (TFAM), and thus enhanced its stability to promote mitochondrial biogenesis. Furthermore, our data indicated that increased mitochondrial Ca 2+ uptake led to increased mitochondrial production of ROS via the upregulation of mitochondrial biogenesis, which subsequently activated NF-κB signaling to accelerate CRC growth. In conclusion, the results indicated that MCU-induced mitochondrial Ca 2+ uptake promotes mitochondrial biogenesis by suppressing phosphorylation of TFAM, thus contributing to CRC cell growth. Our findings reveal a novel mechanism underlying mitochondrial Ca 2+-mediated CRC cell growth and may provide a potential pharmacological target for CRC treatment.

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Section: Discussionsupporting

confidence: 93%

“…An RT-qPCR-based method was employed to measure the relative mtDNA copy number, as previously described. 37 Quantitative reverse transcription PCR (RT-qPCR) analyses Total RNA was isolated from cultured CRC cells or human CRC tissues and reversely transcribed. RT-qPCR was performed as previously described.…”

Section: Knockdown and Overexpression Of Target Genesmentioning

confidence: 99%

MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

Yang

Jin

Wang

et al. 2020

Sig Transduct Target Ther

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“…parasitism or adaptation to freshwater) may be achieved via different evolutionary pathways 99–101 and the consequences for energy demands for an organism may be just one of a plethora of factors including thermal tolerance 102 , aerial exposure 103 , sensitivity to salinity 104 , light 105 or metal concentrations 106 . In addition to the regulation of their transcription and translation 107,108 , mitochondria are very dynamic structures often undergoing continuous fusion, fission and motility, events that can potentially affect their bioenergetic capacities 109 . However, the extent of these rearrangements and the cues that trigger them are still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Comparative mitogenomics of the Decapoda reveals evolutionary heterogeneity in architecture and composition

Tan

Gan

Lee

et al. 2019

Sci Rep

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The emergence of cost-effective and rapid sequencing approaches has resulted in an exponential rise in the number of mitogenomes on public databases in recent years, providing greater opportunity for undertaking large-scale comparative genomic and systematic research. Nonetheless, current datasets predominately come from small and disconnected studies on a limited number of related species, introducing sampling biases and impeding research of broad taxonomic relevance. This study contributes 21 crustacean mitogenomes from several under-represented decapod infraorders including Polychelida and Stenopodidea, which are used in combination with 225 mitogenomes available on NCBI to investigate decapod mitogenome diversity and phylogeny. An overview of mitochondrial gene orders (MGOs) reveals a high level of genomic variability within the Decapoda, with a large number of MGOs deviating from the ancestral arthropod ground pattern and unevenly distributed among infraorders. Despite the substantial morphological and ecological variation among decapods, there was limited evidence for correlations between gene rearrangement events and species ecology or lineage specific nucleotide substitution rates. Within a phylogenetic context, predicted scenarios of rearrangements show some MGOs to be informative synapomorphies for some taxonomic groups providing strong independent support for phylogenetic relationships. Additional comparisons for a range of mitogenomic features including nucleotide composition, strand asymmetry, unassigned regions and codon usage indicate several clade-specific trends that are of evolutionary and ecological interest.

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“…Bottom right: regional variations in mitochondrial distribution allows for subcellular specification of mitochondrial function. Neurons (left from Gao et al, 2019 ) and salivary acinar cells (right from Porat-Shliom et al, 2019 ) both display regional heterogeneity of mitochondrial networks. All images reproduced with permission.…”

Section: Mitochondrial Network Structurementioning

confidence: 99%

“…Mitochondrial network morphology is not only specific to cell types but also demonstrates intracellular heterogeneity. Within a cell, mitochondria positioned at different site-specific regions display different morphology and biochemical properties ( Romashko et al, 1998 ; Kuznetsov et al, 1998 , 2004a , 2006 ; Collins et al, 2002 ; Collins and Bootman, 2003 ; Glancy et al, 2015 ; Benador et al, 2018 ; Porat-Shliom et al, 2019 ; Willingham et al, 2019 ). For example, mitochondrial populations close to the plasma membrane play an important role in functional coupling of ATP guided ion channels (e.g., Ca 2+ entry) ( Lawrie et al, 1996 ).…”

Section: Mitochondrial Network Structurementioning

confidence: 99%

The Functional Impact of Mitochondrial Structure Across Subcellular Scales

et al. 2020

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Mitochondria are key determinants of cellular health. However, the functional role of mitochondria varies from cell to cell depending on the relative demands for energy distribution, metabolite biosynthesis, and/or signaling. In order to support the specific needs of different cell types, mitochondrial functional capacity can be optimized in part by modulating mitochondrial structure across several different spatial scales. Here we discuss the functional implications of altering mitochondrial structure with an emphasis on the physiological trade-offs associated with different mitochondrial configurations. Within a mitochondrion, increasing the amount of cristae in the inner membrane improves capacity for energy conversion and free radical-mediated signaling but may come at the expense of matrix space where enzymes critical for metabolite biosynthesis and signaling reside. Electrically isolating individual cristae could provide a protective mechanism to limit the spread of dysfunction within a mitochondrion but may also slow the response time to an increase in cellular energy demand. For individual mitochondria, those with relatively greater surface areas can facilitate interactions with the cytosol or other organelles but may be more costly to remove through mitophagy due to the need for larger phagophore membranes. At the network scale, a large, stable mitochondrial reticulum can provide a structural pathway for energy distribution and communication across long distances yet also enable rapid spreading of localized dysfunction. Highly dynamic mitochondrial networks allow for frequent content mixing and communication but require constant cellular remodeling to accommodate the movement of mitochondria. The formation of contact sites between mitochondria and several other organelles provides a mechanism for specialized communication and direct content transfer between organelles. However, increasing the number of contact sites between mitochondria and any given organelle reduces the mitochondrial surface area available for contact sites with other organelles as well as for metabolite exchange with cytosol. Though the precise mechanisms guiding the coordinated multi-scale mitochondrial configurations observed in different cell types have yet to be elucidated, it is clear that mitochondrial structure is tailored at every level to optimize mitochondrial function to meet specific cellular demands.

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Mitochondrial Populations Exhibit Differential Dynamic Responses to Increased Energy Demand during Exocytosis In Vivo

Cited by 32 publications

References 36 publications

MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

Comparative mitogenomics of the Decapoda reveals evolutionary heterogeneity in architecture and composition

The Functional Impact of Mitochondrial Structure Across Subcellular Scales

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