Regulation of acid-base transporters by reactive oxygen species following mitochondrial fragmentation

Johnson, D. W.; Allman, Erik; Nehrke, Keith

doi:10.1152/ajpcell.00411.2011

Cited by 20 publications

(14 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been shown that mitochondria dynamically change their morphologies in response to oxidative stress [38]–[40]. Therefore, we tested whether the two striatal cell lines showed different pattern changes in mitochondrial morphology in response to H 2 O 2 .…”

Section: Resultsmentioning

confidence: 99%

Impaired Mitochondrial Dynamics and Nrf2 Signaling Contribute to Compromised Responses to Oxidative Stress in Striatal Cells Expressing Full-Length Mutant Huntingtin

Jin

Gundemir

et al. 2013

PLoS ONE

View full text Add to dashboard Cite

Huntington disease (HD) is an inherited neurodegenerative disease resulting from an abnormal expansion of polyglutamine in huntingtin (Htt). Compromised oxidative stress defense systems have emerged as a contributing factor to the pathogenesis of HD. Indeed activation of the Nrf2 pathway, which plays a prominent role in mediating antioxidant responses, has been considered as a therapeutic strategy for the treatment of HD. Given the fact that there is an interrelationship between impairments in mitochondrial dynamics and increased oxidative stress, in this present study we examined the effect of mutant Htt (mHtt) on these two parameters. STHdhQ111/Q111 cells, striatal cells expressing mHtt, display more fragmented mitochondria compared to STHdhQ7/Q7 cells, striatal cells expressing wild type Htt, concurrent with alterations in the expression levels of Drp1 and Opa1, key regulators of mitochondrial fission and fusion, respectively. Studies of mitochondrial dynamics using cell fusion and mitochondrial targeted photo-switchable Dendra revealed that mitochondrial fusion is significantly decreased in STHdhQ111/Q111 cells. Oxidative stress leads to dramatic increases in the number of STHdhQ111/Q111 cells containing swollen mitochondria, while STHdhQ7/Q7 cells just show increases in the number of fragmented mitochondria. mHtt expression results in reduced activity of Nrf2, and activation of the Nrf2 pathway by the oxidant tBHQ is significantly impaired in STHdhQ111/Q111 cells. Nrf2 expression does not differ between the two cell types, but STHdhQ111/Q111 cells show reduced expression of Keap1 and p62, key modulators of Nrf2 signaling. In addition, STHdhQ111/Q111 cells exhibit increases in autophagy, whereas the basal level of autophagy activation is low in STHdhQ7/Q7 cells. These results suggest that mHtt disrupts Nrf2 signaling which contributes to impaired mitochondrial dynamics and may enhance susceptibility to oxidative stress in STHdhQ111/Q111 cells.

show abstract

Section: Resultsmentioning

confidence: 99%

Impaired Mitochondrial Dynamics and Nrf2 Signaling Contribute to Compromised Responses to Oxidative Stress in Striatal Cells Expressing Full-Length Mutant Huntingtin

Jin

Gundemir

et al. 2013

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…Furthermore, these pathways are not limited to anti-aging responses. For example, mtROS signaling has also been implicated in other homeostatic pathways and processes, including wound healing (Xu and Chisholm, 2014), survival under hypoxia (Schieber and Chandel, 2014), intracellular pH homeostasis (Johnson et al, 2012), cell differentiation (Hamanaka and Chandel, 2010; Hamanaka et al, 2013; Tormos et al, 2011), and innate immunity (West et al, 2011). Accordingly, the remainder of this Review will be devoted to the role of mtROS in whole-body physiology, with the main focus on neuroendocrine control of systemic metabolism in mammals.…”

Section: Mitochondrial Ros Signaling In Organismal Physiology: Lessonmentioning

confidence: 99%

Mitochondrial ROS Signaling in Organismal Homeostasis

Shadel

Horváth

2015

Cell

991

670

View full text Add to dashboard Cite

Summary Generation, transformation, and utilization of organic molecules in support of cellular differentiation, growth, and maintenance are basic tenets that define life. In eukaryotes, mitochondrial oxygen consumption plays a central role in these processes. During the process of oxidative phosphorylation, mitochondria utilize oxygen to generate ATP from organic fuel molecules but in the process also produce reactive oxygen species (ROS). While ROS have long been appreciated for their damage-promoting, detrimental effects, there is now a greater understanding of their roles as signaling molecules. Here, we review mitochondrial ROS-mediated signaling pathways with an emphasis on how they are involved in various basal and adaptive physiological responses that control organismal homeostasis.

show abstract

“…Thapsigargin (Abcam) (Xu et al 2001), mito-TEMPO (Sigma) (Johnson et al 2012), and cyclosporine A (Sigma) (Giacomotto et al 2013) were dissolved in DMSO and added to the NGM media (cooled to 55°) to the appropriate final concentrations, and animals were grown on these plates as previously described.…”

Section: Drug Treatmentsmentioning

confidence: 99%

A γ-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans

Sarasija¹,

Norman

2015

Genetics

View full text Add to dashboard Cite

Mutations in the presenilin (PSEN) encoding genes (PSEN1 and PSEN2) occur in most early onset familial Alzheimer's Disease. Despite the identification of the involvement of PSEN in Alzheimer's Disease (AD) 20 years ago, the underlying role of PSEN in AD is not fully understood. To gain insight into the biological function of PSEN, we investigated the role of the PSEN homolog SEL-12 in Caenorhabditis elegans. Using genetic, cell biological, and pharmacological approaches, we demonstrate that mutations in sel-12 result in defects in calcium homeostasis, leading to mitochondrial dysfunction. Moreover, consistent with mammalian PSEN, we provide evidence that SEL-12 has a critical role in mediating endoplasmic reticulum (ER) calcium release. Furthermore, we found that in SEL-12-deficient animals, calcium transfer from the ER to the mitochondria leads to fragmentation of the mitochondria and mitochondrial dysfunction. Additionally, we show that the impact that SEL-12 has on mitochondrial function is independent of its role in Notch signaling, g-secretase proteolytic activity, and amyloid plaques. Our results reveal a critical role for PSEN in mediating mitochondrial function by regulating calcium transfer from the ER to the mitochondria.KEYWORDS Caenorhabditis elegans; calcium; endoplasmic reticulum; mitochondria; presenilin M ITOCHONDRIA are highly dynamic organelles that are responsible for a myriad of functions including ATP production, generation and metabolism of reactive oxygen species (ROS), and apoptosis (Detmer and Chan 2007). Thus cells, in particular muscle cells and neurons due to their highenergy demands, are extremely reliant on mitochondrial function. Mitochondria also play a critical role in calcium homeostasis by acting as a calcium buffer. Calcium, in turn, regulates mitochondrial morphology, activity, and movement. The relevance of mitochondria is highlighted by the fact that many neurodegenerative diseases, such as Parkinson's and Alzheimer's Disease (AD) are characterized by abnormal mitochondrial activity and morphology (Cali et al. 2012).Mutations in the genes encoding presenilins (PSENs), PSEN1 and PSEN2, are the most common cause of early onset familial Alzheimer's Disease (FAD). PSENs are 50-kDa multipass transmembrane proteins that reside predominantly on the endoplasmic reticulum (ER) (Bezprozvanny and Mattson 2008) and have been shown to be enriched in an ER subcompartment that is in contact with mitochondria (Area-Gomez et al. 2009). Although altered PSEN function has been known to have a role in AD for 20 years (Sherrington et al. 1995), the functional consequences of mutations in PSENs are controversial and not understood. The prevailing model for the pathogenesis of AD is the "amyloid hypothesis," which states that an increase in b amyloid (Ab) 42 peptide is the major cause of neuronal degradation in AD (Hardy and Selkoe 2002); support for this hypothesis stems from the accumulation of amyloid plaques in the brains of AD patients (Hardy 2006). In addition to the "amyloid hypot...

show abstract

Regulation of acid-base transporters by reactive oxygen species following mitochondrial fragmentation

Cited by 20 publications

References 61 publications

Impaired Mitochondrial Dynamics and Nrf2 Signaling Contribute to Compromised Responses to Oxidative Stress in Striatal Cells Expressing Full-Length Mutant Huntingtin

Impaired Mitochondrial Dynamics and Nrf2 Signaling Contribute to Compromised Responses to Oxidative Stress in Striatal Cells Expressing Full-Length Mutant Huntingtin

Mitochondrial ROS Signaling in Organismal Homeostasis

A γ-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans

Contact Info

Product

Resources

About