A Small Molecule Promotes Mitochondrial Fusion in Mammalian Cells

Wang, Danling; Wang, Jianbo; Bonamy, Ghislain M. C.; Meeusen, Shelly; Brusch, Richard G.; Turk, Carolina N.; Yang, Pengyu; Schultz, Peter G.

doi:10.1002/anie.201204589

Cited by 131 publications

(124 citation statements)

References 39 publications

Supporting

Mentioning

119

Contrasting

Order By: Relevance

“…We used a gain of function approach to enhance mitochondrial fusion. Culturing T cells with the ‘fusion promoter’ M1 (Wang et al, 2012), and the ‘fission inhibitor’ Mdivi-1 (Cassidy-Stone et al, 2008) (Figure 3A) induced mitochondrial fusion in IL-2 T E cells, rendering them morphologically similar to IL-15 T M cells (Figure 3B). Treatment with these drugs enhanced other T M cell properties in activated IL-2 T E cells, including increased mitochondrial mass (Figure 3C), OXPHOS and SRC (Figure 3D), CD62L expression (Figure 3E) and robust metabolic activity, as indicated by bioenergetic profiling in response to secondary stimulation with PMA+ionomycin, followed by addition of oligomycin (ATP synthase inhibitor), FCCP, and rotenone with antimycin A (ETC complex I and III inhibitors), all drugs that stress the mitochondria (Figure 3F and S3A).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming

Buck

O’Sullivan

Geltink

et al. 2016

Cell

1,048

1,033

View full text Add to dashboard Cite

SUMMARY Activated effector T (TE) cells augment anabolic pathways of metabolism, such as aerobic glycolysis, while memory T (TM) cells engage catabolic pathways, like fatty acid oxidation (FAO). However, signals that drive these differences remain unclear. Mitochondria are metabolic organelles that actively transform their ultrastructure. Therefore, we questioned whether mitochondrial dynamics controls T cell metabolism. We show that TE cells have punctate mitochondria, while TM cells maintain fused networks. The fusion protein Opa1 is required for TM, but not TE cells after infection and enforcing fusion in TE cells imposes TM cell characteristics and enhances antitumor function. Our data suggest that, by altering cristae morphology, fusion in TM cells configures electron transport chain (ETC) complex associations favoring oxidative phosphorylation (OXPHOS) and FAO, while fission in TE cells leads to cristae expansion, reducing ETC efficiency and promoting aerobic glycolysis. Thus, mitochondrial remodeling is a signaling mechanism that instructs T cell metabolic programming.

show abstract

Section: Resultsmentioning

confidence: 99%

Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming

Buck

O’Sullivan

Geltink

et al. 2016

Cell

1,048

1,033

View full text Add to dashboard Cite

show abstract

“…Thymidine was added to the culture 7-8 h before harvest to measure cell proliferation. When indciated, DCs were pretreated with 0.2 μM M1 26 + 0.1 μM Mdivi-1 27 for 4 h before co-culture with T cells. For in vivo assays by DC transfer method, FLT3L (10 μg/ml in 100 μl PBS) was s.c. injected once daily to WT or Mst1/2 ΔDC mice for 9 consecutive days 28 , and then CD8α + and CD8α − DCs were sorted and pulsed with 20 mg/ml OVA for 1.5 h, washed and i.v.…”

Section: Methodsmentioning

confidence: 99%

Hippo/Mst signalling couples metabolic state and immune function of CD8α+ dendritic cells

Wen

Wang

et al. 2018

Nature

153

145

View full text Add to dashboard Cite

Dendritic cells (DCs) orchestrate the crosstalk between innate and adaptive immunity. CD8α+ DCs present antigens to CD8+ T cells and elicit cytotoxic T-cell responses to viruses, bacteria and tumors1. Although lineage-specific transcriptional regulators of CD8α+ DC development have been identified2, the molecular pathways that selectively orchestrate CD8α+ DC function remain elusive. Moreover, metabolic reprogramming is important for DC development and activation3,4, but metabolic dependence and regulation of DC subsets are unknown. Here, we describe a data-driven systems biology algorithm (NetBID) and an unexpected role of Hippo pathway kinases, Mst1 and Mst2 (Mst1/2), in selectively programming CD8α+ DC function and metabolism. Our NetBID analysis reveals a marked enrichment of the activities of Hippo pathway kinases in CD8α+ DCs relative to CD8α− DCs. DC-specific deletion of Mst1/2, but not Lats1/2 or Yap/Taz that mediate canonical Hippo signaling, disrupts homeostasis and function of CD8+ T cells and anti-tumor immunity. Mst1/2-deficient CD8α+ DCs are impaired in presenting extracellular proteins and cognate peptides to prime CD8+ T cells, while CD8α− DCs lacking Mst1/2 have largely normal function. Mechanistically, compared with CD8α− DCs, CD8α+ DCs show much stronger oxidative metabolism and critically depend upon Mst1/2 signaling to maintain bioenergetic activities and mitochondrial dynamics for functional capacities. Further, CD8α+ DCs selectively express IL-12 that depends upon Mst1/2 and the crosstalk with non-canonical NF-κB signaling. Our findings identify Mst1/2 as selective drivers of CD8α+ DC function by integrating metabolic activity and cytokine signaling, and highlight that the interplay between immune signaling and metabolic reprogramming underlies the unique function of DC subsets.

show abstract

“…These data suggest that mitofusin-mediated metabolic complementation is a candidate target for therapy for mtDNA mutation diseases. The small molecule M1 promotes mitochondrial fusion in mammalian cells [41]. We therefore also decided to test this drug using our UL12.5-GFP retroviral-based system.…”

Section: Mitochondrial 'Initial Metabolic Complementation' Is Dependementioning

confidence: 99%

Mitochondrial fusion provides an ‘initial metabolic complementation’ controlled by mtDNA

Yang

Long

Liu

et al. 2015

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Heteroplasmic cells, harboring both mutant and normal mitochondrial DNAs (mtDNAs), must accumulate mutations to a threshold level before respiratory activity is affected. This phenomenon has led to the hypothesis of mtDNA complementation by inter-mitochondrial content mixing. The precise mechanisms of heteroplasmic complementation are unknown, but it depends both on the mtDNA nucleoid dynamics among mitochondria as well as the mitochondrial dynamics as influenced by mtDNA. We tracked nucleoids among the mitochondria in real time to show that they are shared after complete fusion but not 'kiss-and-run'. Employing a cell hybrid model, we further show that mtDNA-less mitochondria, which have little ATP production and extensive Opa1 proteolytic cleavage, exhibit weak fusion activity among themselves, yet remain competent in fusing with healthy mitochondria in a mitofusin- and OPA1-dependent manner, resulting in restoration of metabolic function. Depletion of mtDNA by overexpression of the matrix-targeted nuclease UL12.5 resulted in heterogeneous mitochondrial membrane potential (ΔΨm) at the organelle level in mitofusin-null cells but not in wild type. In this system, overexpression of mitofusins or application of the fusion-promoting drug M1 could partially rescue the metabolic damage caused by UL12.5. Interestingly, mtDNA transcription/translation is not required for normal mitochondria to restore metabolic function to mtDNA-less mitochondria by fusion. Thus, interplay between mtDNA and fusion capacity governs a novel 'initial metabolic complementation'.

show abstract

A Small Molecule Promotes Mitochondrial Fusion in Mammalian Cells

Cited by 131 publications

References 39 publications

Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming

Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming

Hippo/Mst signalling couples metabolic state and immune function of CD8α+ dendritic cells

Mitochondrial fusion provides an ‘initial metabolic complementation’ controlled by mtDNA

Contact Info

Product

Resources

About