Bioenergetic analysis of isolated cerebrocortical nerve terminals on a microgram scale: spare respiratory capacity and stochastic mitochondrial failure

Choi, Sung Won; Gerencser, Akos A.; Nicholls, David G.

doi:10.1111/j.1471-4159.2009.06055.x

Cited by 189 publications

(216 citation statements)

References 51 publications

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“…Isolated rat heart or liver mitochondria were aliquoted into a XF96 microplate (Seahorse Bioscience) (49). AT 2 R agonist and antagonist and an arginine analog that inhibits NO production (L-NAME) were added individually or combined, and oxygen consumption rates were determined by using a compartment model-based algorithm.…”

Section: Methodsmentioning

confidence: 99%

Identification and characterization of a functional mitochondrial angiotensin system

Abadir

Foster²,

Crow

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

250

251

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The renin-angiotensin (Ang) system regulates multiple physiological functions through Ang II type 1 and type 2 receptors. Prior studies suggest an intracellular pool of Ang II that may be released in an autocrine manner upon stretch to activate surface membrane Ang receptors. Alternatively, an intracellular renin-Ang system has been proposed, with a primary focus on nuclear Ang receptors. A mitochondrial Ang system has not been previously described. Here we report that functional Ang II type 2 receptors are present on mitochondrial inner membranes and are colocalized with endogenous Ang. We demonstrate that activation of the mitochondrial Ang system is coupled to mitochondrial nitric oxide production and can modulate respiration. In addition, we present evidence of age-related changes in mitochondrial Ang receptor expression, i.e., increased mitochondrial Ang II type 1 receptor and decreased type 2 receptor density that is reversed by chronic treatment with the Ang II type 1 receptor blocker losartan. The presence of a functional Ang system in human mitochondria provides a foundation for understanding the interaction between mitochondria and chronic disease states and reveals potential therapeutic targets for optimizing mitochondrial function and decreasing chronic disease burden with aging.

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Section: Methodsmentioning

confidence: 99%

Identification and characterization of a functional mitochondrial angiotensin system

Abadir

Foster²,

Crow

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

250

251

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show abstract

“…Importantly, the MTCH2 knockout enriched progenitors also possess substantial mitochondrial spare respiratory capacity (SRC; Fig. 2a, right panel), which is the extra capacity available in cells to produce energy in response to increased stress and as such is associated with cellular survival 21 . Similar observations have been recently reported, where a deficiency in the glycolytic enzyme lactate dehydrogenase A (LDHA) induces HSC differentiation and is accompanied by an increase in mitochondrial OXPHOS and SRC in HSPCs 22 .…”

Section: Loss Of Mtch2 Impairs Hsc Homeostasismentioning

confidence: 99%

An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate

et al. 2015

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The metabolic state of stem cells is emerging as an important determinant of their fate. In the bone marrow, haematopoietic stem cell (HSC) entry into cycle, triggered by an increase in intracellular reactive oxygen species (ROS), corresponds to a critical metabolic switch from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). Here we show that loss of mitochondrial carrier homologue 2 (MTCH2) increases mitochondrial OXPHOS, triggering HSC and progenitor entry into cycle. Elevated OXPHOS is accompanied by an increase in mitochondrial size, increase in ATP and ROS levels, and protection from irradiation-induced apoptosis. In contrast, a phosphorylation-deficient mutant of BID, MTCH2's ligand, induces a similar increase in OXPHOS, but with higher ROS and reduced ATP levels, and is associated with hypersensitivity to irradiation. Thus, our results demonstrate that MTCH2 is a negative regulator of mitochondrial OXPHOS downstream of BID, indispensible in maintaining HSC homeostasis.

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“…37,38 Briefly, cortex tissue was rapidly removed and homogenized in ice-cold sucrose medium (320 mM sucrose, 1 mM EDTA, 0.25 mM DTT (pH 7.4). The homogenate was then centrifuged at 1,000 Â g for 10 min at 4 C. The supernatant was carefully layered on top of a discontinuous Percoll gradient (3-mL layers of 3%, 10%, and 23% Percoll in sucrose medium) in a centrifuge tube and centrifuged at 32,500 Â g for 10 min at 4 C. Synaptosomes were collected as the band between 10% and 23% Percoll.…”

Section: Synaptosome Isolation and Mitochondrial Respiration Assaymentioning

confidence: 99%

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization

et al. 2017

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Dominant missense mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the cytoplasmic accumulation of TDP-43 represents a pathological hallmark in ALS and frontotemporal lobar degeneration (FTD). Behavioral investigation of the transgenic mouse model expressing the disease-causing human TDP-43 M337V mutant (TDP-43 M337V mice) is encumbered by premature death in homozygous transgenic mice and a reported lack of phenotype assessed by tail elevation and footprint in hemizygous transgenic mice. Here, using a battery of motor-coordinative and cognitive tests, we report robust motor-coordinative and cognitive deficits in hemizygous TDP-43 M337V mice by 8 months of age. After 12 months of age, cortical neurons are significantly affected by the mild expression of mutant TDP-43, characterized by cytoplasmic TDP-43 mislocalization, mitochondrial dysfunction, and neuronal loss. Compared with age-matched non-transgenic mice, TDP-43 M337V mice demonstrate a similar expression of total TDP-43 but higher levels of TDP-43 in mitochondria. Interestingly, a TDP-43 mitochondrial localization inhibitory peptide abolishes cytoplasmic TDP-43 accumulation, restores mitochondrial function, prevents neuronal loss, and alleviates motor-coordinative and cognitive deficits in adult hemizygous TDP-43 M337V mice. Thus, this study suggests hemizygous TDP-43 M337V mice as a useful animal model to study TDP-43 toxicity and further consolidates mitochondrial TDP-43 as a novel therapeutic target for TDP-43-linked neurodegenerative diseases.

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Bioenergetic analysis of isolated cerebrocortical nerve terminals on a microgram scale: spare respiratory capacity and stochastic mitochondrial failure

Cited by 189 publications

References 51 publications

Identification and characterization of a functional mitochondrial angiotensin system

Identification and characterization of a functional mitochondrial angiotensin system

An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization

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