Mitochondria—hubs for regulating cellular biochemistry: emerging concepts and networks

Anderson, Alexander; Jackson, Thomas Daniel; Stroud, David A.; Stojanovski, Diana

doi:10.1098/rsob.190126

Cited by 86 publications

(66 citation statements)

References 204 publications

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“…The mitochondria are a hub of major metabolic processes and also regulate cell fate [21]. However, several aspects of metabolic control by the mitochondria in the pathogenesis of diseases are still not well defined.…”

Section: Discussionmentioning

confidence: 99%

Complex III Inhibition-Induced Pulmonary Hypertension Affects the Mitochondrial Proteomic Landscape

James

Varghese

Vasilyev

et al. 2020

IJMS

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The mitochondria play a vital role in controlling cell metabolism and regulating crucial cellular outcomes. We previously demonstrated that chronic inhibition of the mitochondrial complex III in rats by Antimycin A (AA) induced sustained pulmonary vasoconstriction. On the metabolic level, AA-induced mitochondrial dysfunction resulted in a glycolytic shift that was reported as the primary contributor to pulmonary hypertension pathogenesis. However, the regulatory proteins driving this metabolic shift with complex III inhibition are yet to be explored. Therefore, to delineate the mechanisms, we followed changes in the rat lung mitochondrial proteome throughout AA treatment. Rats treated with AA for up to 24 days showed a disturbed mitochondrial proteome with significant changes in 28 proteins (p < 0.05). We observed a time-dependent decrease in the expression of key proteins that regulate fatty acid oxidation, the tricarboxylic acid cycle, the electron transport chain, and amino acid metabolism, indicating a correlation with diminished mitochondrial function. We also found a significant dysregulation in proteins that controls the protein import machinery and the clearance and detoxification of oxidatively damaged peptides via proteolysis and mitophagy. This could potentially lead to the onset of mitochondrial toxicity due to misfolded protein stress. We propose that chronic inhibition of mitochondrial complex III attenuates mitochondrial function by disruption of the global mitochondrial metabolism. This potentially aggravates cellular proliferation by initiating a glycolytic switch and thereby leads to pulmonary hypertension.

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Section: Discussionmentioning

confidence: 99%

Complex III Inhibition-Induced Pulmonary Hypertension Affects the Mitochondrial Proteomic Landscape

James

Varghese

Vasilyev

et al. 2020

IJMS

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“…Calcium enters into mitochondria through the VDAC channel localized on the outer membrane (Tan and Colombini, 2007), and is transported across the intermembrane space and the inner membrane into the matrix by the mitochondrial calcium uniporter (MCU) and its docking/regulatory proteins MICU1/MICU2 (Tan and Colombini, 2007). Similarly, calcium is exported from the mitochondrial matrix through LETM1 or the Na + /Ca 2+ exchanger NCLX, in exchange for H + or Na + /Li + , respectively and, then, across the outer membrane through VDAC and the isoform 3 of the sodium calcium exchanger (NCX3; Tan and Colombini, 2007;Scorziello et al, 2013;Anderson et al, 2019). In PD neurons, the activation of mitochondrial Na + /Ca 2+ exchanger (mNCX) is the primary mechanism by which mitochondrial calcium concentrations [Ca 2+ ] m is returned to the cytoplasm, and therefore it is critical to a multitude of Ca 2+ -dependent processes including neurotransmitters release, synaptic plasticity, bioenergetics and mitochondrial nitric oxide (NO), and reactive oxygen species (ROS) production (Castaldo et al, 2009;Cali et al, 2013).…”

Section: Mitochondrial Calcium Homeostasis In Pdmentioning

confidence: 99%

Mitochondrial Homeostasis and Signaling in Parkinson’s Disease

Scorziello

Borzacchiello

Sisalli

et al. 2020

Front. Aging Neurosci.

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The loss of dopaminergic (DA) neurons in the substantia nigra leads to a progressive, long-term decline of movement and other non-motor deficits. The symptoms of Parkinson's disease (PD) often appear later in the course of the disease, when most of the functional dopaminergic neurons have been lost. The late onset of the disease, the severity of the illness, and its impact on the global health system demand earlier diagnosis and better targeted therapy. PD etiology and pathogenesis are largely unknown. There are mutations in genes that have been linked to PD and, from these complex phenotypes, mitochondrial dysfunction emerged as central in the pathogenesis and evolution of PD. In fact, several PD-associated genes negatively impact on mitochondria physiology, supporting the notion that dysregulation of mitochondrial signaling and homeostasis is pathogenically relevant. Derangement of mitochondrial homeostatic controls can lead to oxidative stress and neuronal cell death. Restoring deranged signaling cascades to and from mitochondria in PD neurons may then represent a viable opportunity to reset energy metabolism and delay the death of dopaminergic neurons. Here, we will highlight the relevance of dysfunctional mitochondrial homeostasis and signaling in PD, the molecular mechanisms involved, and potential therapeutic approaches to restore mitochondrial activities in damaged neurons.

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“…membrane is a platform for the NLRP3 inflammasome [266]. There exist several known signal transduction pathways between the cell and its mitochondria [267] The glycolytic pathway is vital for monocyte function and monocyte-derived cells' differentiation and functions (see Table 8): (i) the glycolytic pathway influences monocyte differentiation into macrophages and dendritic cells [261,[276][277][278]; (ii) glycolysis is upregulated in monocytes in response to infection and is important for effector functions [279][280][281], and the Akt-mTOR-HIF-1-α pathway seems especially important [268,[276][277][278]; (iii) trained monocytes are mainly glycolytic [94,245,282].…”

Section: Mmp9mentioning

confidence: 99%

Standardization of sampling and sample preparation for analysis of human monocyte subsets in peripheral blood

Rundgren

Bruserud

Ryningen

et al. 2018

Journal of Immunological Methods

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Mitochondria—hubs for regulating cellular biochemistry: emerging concepts and networks

Cited by 86 publications

References 204 publications

Complex III Inhibition-Induced Pulmonary Hypertension Affects the Mitochondrial Proteomic Landscape

Complex III Inhibition-Induced Pulmonary Hypertension Affects the Mitochondrial Proteomic Landscape

Mitochondrial Homeostasis and Signaling in Parkinson’s Disease

Standardization of sampling and sample preparation for analysis of human monocyte subsets in peripheral blood

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