A new live-cell reporter strategy to simultaneously monitor mitochondrial biogenesis and morphology

Nilsson, Linn Iren Hodneland; Pettersen, Ina Katrine Nitschke; Nikolaisen, Julie; Micklem, David; Dale, Hege Avsnes; Røsland, Gro Vatne; Lorens, James B.; Tronstad, Karl Johan

doi:10.1038/srep17217

Cited by 18 publications

(23 citation statements)

References 41 publications

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“…We tested this using the live-cell reporter, NRF1mitoGFP, which contains an NRF1 binding sequence driving GFP protein expression fused with a mitochondrial localization signal. This allowed us to simultaneously monitor NRF1-mediated transcriptional activity as well as mitochondrial morphology (Hodneland Nilsson et al, 2015). As predicted from the NRF1 nuclear localization, we observed that moderate but chronic depletion of ATP induced NRF1-mediated transcription ( Fig.7D and S4D).…”

Section: Atp Depletion Activates Atm With Downstream Effects On Nrf1supporting

confidence: 66%

ATM is activated by ATP depletion and modulates mitochondrial function through NRF1

Chow

Cheng

Song

et al. 2018

Preprint

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Oxidative stress, resulting from neuronal activity and depleted ATP levels, activates ATM, which phosphorylates NRF1, causing nuclear translocation and upregulation of mitochondrial gene expression. In ATM deficiency, ATP levels recover more slowly, particularly in active neurons with high energy demands. AbstractWe have uncovered new insights into the symptoms of ataxia-telangiectasia (A-T). Neurons with high physiological activity, particularly cerebellar Purkinje cells, have large and dynamic ATP demands. Depletion of ATP generates reactive oxygen species that activate ATM (the A-T Mutated gene product). Activated in this way, but not by DNA damage, ATM phosphorylates nuclear respiratory factor-1 (NRF1). This leads to NRF1 dimerization, nuclear translocation and the upregulation of nuclear-encoded mitochondrial genes, thus enhancing the capacity of the electron transport chain (ETC) and restoring mitochondrial function. In cells with ATM deficiency, resting ATP levels are normal, but cells replenish ATP poorly following surges in energy demand and chronic ATP insufficiency endangers cell survival. This is a particular problem for energyintensive cells such as Purkinje cells, which degenerate in A-T. Our findings thus identify ATM as a guardian of mitochondrial output as well as genomic integrity, and suggest that alternate fuel sources may ameliorate A-T disease symptoms.

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Section: Atp Depletion Activates Atm With Downstream Effects On Nrf1supporting

confidence: 66%

ATM is activated by ATP depletion and modulates mitochondrial function through NRF1

Chow

Cheng

Song

et al. 2018

Preprint

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“…Since MitoTracker-labeled MT can leak dye over time, control experiments were necessary to confirm the real uptake of MT. To overcome the limitation of dye fading in this case, the use of cells with a stable MT reporter [16] will allow improved monitoring of this phenomenon, including more precise quantitation of biodistribution and fate at longer time points. MT trafficking was found to be independent of pre-conditioning, proinflammatory, or anti-oxidant treatment of MSCs or mitogen stimulation of target PBMCs.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo, we could also evidence the natural transfer of MT in response to intraperitoneal infusion of MSCs in immune-competent mice. To overcome the limitation of dye fading in this case, the use of cells with a stable MT reporter [16] will allow improved monitoring of this phenomenon, including more precise quantitation of biodistribution and fate at longer time points.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response

et al. 2020

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Mesenchymal stem cells (MSCs) have fueled ample translation for the treatment of immune-mediated diseases. They exert immunoregulatory and tissue-restoring effects. MSC-mediated transfer of mitochondria (MitoT) has been demonstrated to rescue target organs from tissue damage, yet the mechanism remains to be fully resolved. Therefore, we explored the effect of MitoT on lymphoid cells. Here, we describe dose-dependent MitoT from mitochondria-labeled MSCs mainly to CD4 + T cells, rather than CD8 + T cells or CD19 + B cells. Artificial transfer of isolated MSCderived mitochondria increases the expression of mRNA transcripts involved in T-cell activation and T regulatory cell differentiation including FOXP3, IL2RA, CTLA4, and TGFb1, leading to an increase in a highly suppressive CD25 + FoxP3 + population. In a GVHD mouse model, transplantation of MitoT-induced human T cells leads to significant improvement in survival and reduction in tissue damage and organ T CD4 + , CD8 + , and IFN-c + expressing cell infiltration. These findings point to a unique CD4 + T-cell reprogramming mechanism with pre-clinical proof-of-concept data that pave the way for the exploration of organelle-based therapies in immune diseases.

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“…Interestingly, by culturing fibroblasts on micropatterned coverslips of various sizes, it was shown that mitochondrial network volume primarily depends on the size and shape of the cell (Chevrollier et al, 2012). Shape complexity of individual mitochondria can be described by several parameters, such as ‘solidity’ (compactness) (Westrate et al, 2014), ‘tortuosity’ (for twisted mitochondria) (Lihavainen et al, 2012) ‘Feret ratio’ (ratio between length and width, a descriptor of filamentous character) (Hodneland Nilsson et al, 2015), or Form Factor (a combined measure of mitochondrial length and degree of branching) (Koopman et al, 2008). Other morphological parameters, like the number of branches or branch intersections, give an estimation of shape complexity at the level of the mitochondrial network (Lihavainen et al, 2012; Nikolaisen et al, 2014; Westrate et al, 2014).…”

Section: Descriptions Of Mitochondrial Morphologymentioning

confidence: 99%

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

Aouacheria

Baghdiguian

Lamb

et al. 2017

Neurochemistry International

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The morphology of a population of mitochondria is the result of several interacting dynamical phenomena, including fission, fusion, movement, elimination and biogenesis. Each of these phenomena is controlled by underlying molecular machinery, and when defective can cause disease. New understanding of the relationships between form and function of mitochondria in health and disease is beginning to be unraveled on several fronts. Studies in mammals and model organisms have revealed that mitochondrial morphology, dynamics and function appear to be subject to regulation by the same proteins that regulate apoptotic cell death. One protein family that influences mitochondrial dynamics in both healthy and dying cells is the Bcl-2 protein family. Connecting mitochondrial dynamics with life-death pathway forks may arise from the intersection of Bcl-2 family proteins with the proteins and lipids that determine mitochondrial shape and function. Bcl-2 family proteins also have multifaceted influences on cells and mitochondria, including calcium handling, autophagy and energetics, as well as the subcellular localization of mitochondrial organelles to neuronal synapses. The remarkable range of physical or functional interactions by Bcl-2 family proteins is challenging to assimilate into a cohesive understanding. Most of their effects may be distinct from their direct roles in apoptotic cell death and are particularly apparent in the nervous system. Dual roles in mitochondrial dynamics and cell death extend beyond BCL-2 family proteins. In this review, we discuss many processes that govern mitochondrial structure and function in health and disease, and how Bcl-2 family proteins integrate into some of these processes.

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A new live-cell reporter strategy to simultaneously monitor mitochondrial biogenesis and morphology

Cited by 18 publications

References 41 publications

ATM is activated by ATP depletion and modulates mitochondrial function through NRF1

ATM is activated by ATP depletion and modulates mitochondrial function through NRF1

Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

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