Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids

Abdullah, Mahmud O; Zeng, Renpan; Margerum, Chelsea L; Papadopoli, David; Monnin, Cian; Punter, Kaylee B; Chu, Charles; Al-Rofaidi, Mohammad; Al‐Tannak, Naser F.; Berardi, Domenica; Rattray, Zahra; Rattray, Nicholas A.; Abraham, Sheela A.; Eskelinen, Eeva‐Liisa; Watson, David; Avizonis, Daina; Topisirović, Ivan; Chan, Edmond Y W

doi:10.1016/j.celrep.2022.111198

Cited by 16 publications

(10 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with the idea that mitochondrial fusion is associated with low mitochondrial heat output, the cell line with the greatest inferred temperature difference between the two methods used in the present study to assess mitochondrial temperature, and also the one where this difference was the most variable experimentally, was U2OS ( Figure 3E ), a cell line in which mitochondria are mostly filamentous, e.g., see Westrate et al, 2014 . In other cell lines, such as iMEFs, mitochondria are highly fragmented under standard culture conditions, e.g., see Abdullah et al, 2022 .…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial temperature homeostasis resists external metabolic stresses

Terzioglu,

Veeroja,

Montonen

et al. 2023

eLife

View full text Add to dashboard Cite

Based on studies with a fluorescent reporter dye, Mito Thermo Yellow, and the genetically encoded gTEMP ratiometric fluorescent temperature indicator targeted to mitochondria, the temperature of active mitochondria in four mammalian and one insect cell-line was estimated to be up to 15 °C above that of the external environment to which the cells were exposed. High mitochondrial temperature was maintained in the face of a variety of metabolic stresses, including substrate starvation or modification, decreased ATP demand due to inhibition of cytosolic protein synthesis, inhibition of the mitochondrial adenine nucleotide transporter and, if an auxiliary pathway for electron transfer was available via the alternative oxidase, even respiratory poisons acting downstream of complex I. We propose that the high temperature of active mitochondria is an inescapable consequence of the biochemistry of oxidative phosphorylation and is homeostatically maintained as a primary feature of mitochondrial metabolism. Mitochondria are at least 15 °C hotter than their external environment in living cells. In response to diverse metabolic stresses, mitochondrial temperature re-adjusts to this value whenever possible.

show abstract

Section: Discussionmentioning

confidence: 99%

Mitochondrial temperature homeostasis resists external metabolic stresses

Terzioglu,

Veeroja,

Montonen

et al. 2023

eLife

View full text Add to dashboard Cite

show abstract

“…Collectively, the data indicate that Allo promoted astrocytic mitochondrial biogenesis through NRF1-TFAM activation and increased DRP1/OPA1 protein ratio to reverse stress-induced hyperfused mitochondrial network to restore mitochondrial and bioenergetic homeostasis ( 57 ).…”

Section: Resultsmentioning

confidence: 99%

Allopregnanolone pleiotropic action in neurons and astrocytes: calcium signaling as a unifying mechanism

Wang,

Chen,

Mao

et al. 2023

Front. Endocrinol.

View full text Add to dashboard Cite

ObjectiveAllopregnanolone (Allo) is a neurosteroid with pleiotropic action in the brain that includes neurogenesis, oligogenesis, human and rodent neural stem cell regeneration, increased glucose metabolism, mitochondrial respiration and biogenesis, improved cognitive function, and reduction of both inflammation and Alzheimer’s disease (AD) pathology. Because the breadth of Allo-induced responses requires activation of multiple systems of biology in the absence of an Allo-specific nuclear receptor, analyses were conducted in both neurons and astrocytes to identify unifying systems and signaling pathways.MethodsMechanisms of Allo action were investigated in embryonic hippocampal neurons and astrocytes cultured in an Aging Model (AM) media. Cellular morphology, mitochondrial function, and transcriptomics were investigated followed by mechanistic pathway analyses.ResultsIn hippocampal neurons, Allo significantly increased neurite outgrowth and synaptic protein expression, which were paralleled by upregulated synaptogenesis and long-term potentiation gene expression profiles. Mechanistically, Allo induced Ca2+/CREB signaling cascades. In parallel, Allo significantly increased maximal mitochondrial respiration, mitochondrial membrane potential, and Complex IV activity while reducing oxidative stress, which required both the GABAA and L-type Ca2+ channels. In astrocytes, Allo increased ATP generation, mitochondrial function and dynamics while reducing oxidative stress, inflammasome indicators, and apoptotic signaling. Mechanistically, Allo regulation of astrocytic mitochondrial function required both the GABAA and L-type Ca2+ channels. Furthermore, Allo activated NRF1-TFAM signaling and increased the DRP1/OPA1 protein ratio, which led to increased mitochondrial biogenesis and dynamics.ConclusionCollectively, the cellular, mitochondrial, transcriptional, and pharmacological profiles provide evidence in support of calcium signaling as a unifying mechanism for Allo pleiotropic actions in the brain.

show abstract

“…Cellular stress, such as serum or amino acid deprivation or acidosis has previously been shown to increase mitochondrial length. 39 , 40 This process was named stress-induced mitochondrial hyperfusion (SIMH) and represents an adaptive pro-survival response against stresses requiring L-OPA1 isoform. Decreased ΔΨm promotes L-OPA1 isoforms cleavage to S-OPA1 by activation of OMA1 proteases 41 , 42 and further inhibits the fusion of the inner membrane and induces fission of the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission

Lhuissier,

Desquiret-Dumas,

Girona

et al. 2024

iScience

View full text Add to dashboard Cite

Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids

Cited by 16 publications

References 103 publications

Mitochondrial temperature homeostasis resists external metabolic stresses

Mitochondrial temperature homeostasis resists external metabolic stresses

Allopregnanolone pleiotropic action in neurons and astrocytes: calcium signaling as a unifying mechanism

Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission

Contact Info

Product

Resources

About