Mitochondrial stress: A bridge between mitochondrial dysfunction and metabolic diseases?

doi:10.1016/j.cellsig.2011.05.008

Cellular Signalling

Volume 23, Issue 10, October 2011, Pages 1528-1533

https://doi.org/10.1016/j.cellsig.2011.05.008 Get rights and content

Abstract

Under pathophysiological conditions such as obesity, excessive oxidation of nutrients may induce mitochondrial stress, leading to mitochondrial unfolded protein response (UPR^mt) and initiation of a retrograde stress signaling pathway. Defects in the UPR^mt and the retrograde signaling pathways may disrupt the integrity and homeostasis of the mitochondria, resulting in endoplasmic reticulum stress and insulin resistance. Improving the capacity of mitochondria to reduce stress may be an effective approach to improve mitochondria function and to suppress obesity-induced metabolic disorders such as insulin resistance and type 2 diabetes.

Introduction

Metabolic syndrome, which is characterized by a combination of several metabolic risk factors including abdominal obesity, insulin resistance, hypertension, and atherogenic dyslipidemia, is one of the most common health problems in modern society. The causes of metabolic syndrome are complicated involving the interaction of various genetic and environmental components [1], [2], [3] and changes of life style [4]. However, the fundamental mechanisms underlying metabolic syndrome remain largely unclear.

Metabolic homeostasis is largely dependent on mitochondria. Known as "cellular power plants" for most eukaryotic cells, mitochondria metabolize nutrients to produce the “energy currency” ATP for normal cell function. Changes in mitochondrial activity, which could be induced by genetic and external factors such as nutrients, hormones, temperature, exercise, hypoxia and aging, may have a great impact on various cellular activities such as growth, proliferation, and survival [5], [6], [7], [8]. Mitochondrial dysfunction is central to many chronic diseases, ranging from major metabolic disorders such as obesity, insulin resistance, type 2 diabetes to cardiovascular disease, cancer and aging-associated neurodegenerative diseases [6], [8], [9], [10], [11]. However, whether mitochondrial dysfunction is a cause or a consequence of these diseases remains elusive.

In this review, we have summarized our current understanding of the potential role of mitochondrial dysfunction in metabolic disorders, highlighting mitochondrial stress as a potential mechanism linking mitochondrial dysfunction to metabolic diseases.

Section snippets

Mitochondrial dysfunction is closely associated with metabolic disorders

As a cellular power plant, the central and most important function of mitochondria is the synthesis of ATP by oxidative phosphorylation (OXPHOS), a process by which mitochondria generate energy through oxidation of nutrients such as free fatty acids to create an electron chemical gradient across the mitochondrial inner membrane. This electron chemical gradient is used as a source of potential energy to generate ATP, transport substrates or ions, or produce heat [6]. Oxygen radicals, e.g.

Quality control system in mitochondria

Under pathophysiological conditions such as obesity, nutrient overloading may lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) causing ER stress. To maintain ER homeostasis, cells initiate an ER-specific unfolded protein response (UPR^er) that alleviates ER stress through chaperon-mediated protein folding, protein quality control (QC), and misfolded protein degradation. Recent studies suggest that mitochondria have a similar unfolded protein response (UPR^mt) and

Mitochondrial stress and unfolded protein response

Metabolic stimuli and other changes within mitochondria can result in broad changes in nuclear gene expression via retrograde mitochondrial to nuclear signaling. These responses are generally referred to as mitochondrial stress responses. Early studies found that mitochondrial stress is caused by altered mitochondrial membrane potential or uncoupling of OXPHOS [41]. Later studies show that accumulation of unfolded proteins in the organelle also triggers UPR^mt [42], [43], [44]. A number of

Cross-talk between mitochondria and ER during stress

Mitochondria and ER form a delicate network connection that is fundamental for the maintenance of cellular homeostasis and survival. In addition to a structural connection [72], there is a direct transfer of lipids between the ER and mitochondria [73]. Furthermore, there is dynamic exchange of Ca²⁺ ions between these two organelles, which regulates processes such as ER chaperone-assisted folding of newly synthesized proteins, regulation of mitochondria-localized dehydrogenases involved in

Conclusion remarks: Is mitochondrial stress a bridge between mitochondrial dysfunction and insulin resistance?

Mitochondria are vital for cell function and survival, and it is not surprising that the integrity of this organelle is safeguarded by various QC mechanisms such as UPR^mt and MAD. Like UPR^er, UPR^mt senses perturbations of protein homeostasis in mitochondria and, in turn, activates genes that encoding QC proteins such as mitochondrial chaperons and proteases, leading to enhanced mitochondrial protein-handling capacity and protein homeostasis [40], [45], [46], [47]. The ultimate outcome of this

References (94)

J. Hebebrand et al.
Child Adolesc Psychiatr Clin N Am
(2009)
E.J. Lesnefsky et al.
J Mol Cell Cardiol
(2001)
H.M. McBride et al.
Curr Biol
(2006)
K. Hojlund et al.
Endocrinol Metab Clin North Am
(2008)
A. De Pauw et al.
Am J Pathol
(2009)
J.F. Dumas et al.
Diabetes Metab
(2009)
B. Fromenty et al.
Pharmacol Ther
(1995)
M. Perez-Carreras et al.
Hepatology
(2003)
D. Pessayre et al.
J Hepatol
(2005)
C. Mitchell et al.
Am J Pathol
(2009)

B. Bukau et al.

Cell

(1998)

D.A. Bota et al.

Free Radic Biol Med

(2005)

G. Ondrovicova et al.

J Biol Chem

(2005)

S.G. Kang et al.

J Biol Chem

(2005)

J.M. Flynn et al.

Mol Cell

(2003)

C.M. Haynes et al.

Dev Cell

(2007)

S.A. Broadley et al.

Trends Cell Biol

(2008)

M.T. Ryan et al.

Gene

(1997)

T.W. Fawcett et al.

J Biol Chem

(1996)

H. Puthalakath et al.

Cell

(2007)

R.A. Butow et al.

Mol Cell

(2004)

T. Imatoh et al.

Diabetes Res Clin Pract

(2009)

E. Lindholm et al.

J Diabetes Complications

(2004)

J. Durieux et al.

Cell

(2011)

C. Giorgi et al.

Int J Biochem Cell Biol

(2009)

M. Beller et al.

FEBS Lett

(2010)

J.P. Lievremont et al.

J Biol Chem

(1997)

R.K. Reddy et al.

J Biol Chem

(2003)

T. Hayashi et al.

Cell

(2007)

A. Burkart et al.

J Biol Chem

(2011)

J.D. Malhotra et al.

Semin Cell Dev Biol

(2007)

J.M. Heo et al.

Mol Cell

(2010)

M. Chatenay-Lapointe et al.

Cell Metab

(2010)

J. Kirstein-Miles et al.

Cell Metab

(2010)

R.L. Pollex et al.

Nat Clin Pract Cardiovasc Med

(2006)

A. Hinney et al.

Obes Facts

(2008)

M.T. Hamilton et al.

Diabetes

(2007)

P. Ritz et al.

Diabetes Metab

(2005)

D.C. Wallace

Annu Rev Genet

(2005)

M. Frisard et al.

Endocrine

(2006)

J.A. Kim et al.

Circ Res

(2008)

K. Henze et al.

Nature

(2003)

D.E. Kelley et al.

Diabetes

(2002)

A. Wiederkehr et al.

Endocrinology

(2006)

H. Ashrafian et al.

Circulation

(2007)

M.A. Abdul-Ghani et al.

Curr Diab Rep

(2008)

K.R. Short et al.

Proc Natl Acad Sci USA

(2005)

Cited by (90)

The application of brain organoid for drug discovery in mitochondrial diseases
2024, International Journal of Biochemistry and Cell Biology
Mitochondrial diseases are difficult to treat due to the complexity and multifaceted nature of mitochondrial dysfunction. Brain organoids are three-dimensional (3D) structures derived from human pluripotent stem cells designed to mimic brain-like development and function. Brain organoids have received a lot of attention in recent years as powerful tools for modeling human diseases, brain development, and drug screening. Screening compounds for mitochondrial diseases using brain organoids could provide a more physiologically relevant platform for drug discovery. Brain organoids offer the possibility of personalized medicine because they can be derived from patient-specific cells, allowing testing of drugs tailored to specific genetic mutations. In this article, we highlight how brain organoids offer a promising avenue for screening compounds for mitochondrial diseases and address the challenges and limitations associated with their use. We hope this review will provide new insights into the further progress of brain organoids for mitochondrial screening studies.
Extracellular nanovesicles produced by Bacillus licheniformis: A potential anticancer agent for breast and lung cancer
2023, Microbial Pathogenesis
Cancer is a major public burden and leading cause of death worldwide; furthermore, it is a significant barrier to increasing life expectancy in most countries of the world. Among various types of cancers, breast and lung cancers lead to significant mortality in both males and females annually. Bacteria-derived products have been explored for their use in cancer therapy. Although bacteria contain significant amounts of anticancer substances, attenuated bacteria may still pose a potential risk for infection owing to the variety of immunomodulatory molecules present in the parental bacteria; therefore, non-cellular bacterial extracellular vesicles (BEVs), which are naturally non-replicating, safer, and are considered to be potential anticancer agents, are preferred for cancer therapy. Gram-positive bacteria actively secrete cytoplasmic membrane vesicles that are spherical and vary between 10 and 400 nm in size. However, no studies have considered cytoplasmic membrane vesicles derived from Bacillus licheniformisin cancer treatment. In this study, we investigated the potential use of B. licheniformis extracellular nanovesicles (BENVs) as therapeutic agents to treat cancer. Purified BENVs from the culture supernatant of B. licheniformis using ultracentrifugation and ExoQuick were characterized using a series of analytical techniques. Human breast cancer cells (MDA-MB-231) and lung cancer cells (A549) were treated with different concentrations of purified BENVs, which inhibited the cell viability and proliferation, and increased cytotoxicity in a dose-dependent manner. To elucidate the mechanism underlying the anticancer activity of BENVs, the oxidative stress markers such as reactive oxygen species (ROS) and glutathione (GSH) levels were measured. The ROS levels were significantly higher in BENV-treated cells, whereas the GSH levels were markedly reduced. Cells treated with BENVs, doxorubicin (DOX), or a combination of BENVs and DOX showed significantly increased expression of p53, p21, caspase-9/3, and Bax, and concomitantly decreased expression of Bcl-2. The combination of BENVs and doxorubicin enhanced mitochondrial dysfunction, DNA damage, and apoptosis. To our knowledge, this is the first study to determine the anticancer properties of BENVs derived from industrially significant probacteria on breast and lung cancer cells.
NRF2/PGC-1α-mediated mitochondrial biogenesis contributes to T-2 toxin-induced toxicity in human neuroblastoma SH-SY5Y cells
2022, Toxicology and Applied Pharmacology
Citation Excerpt :
Mitochondria are one of the main sources of cellular ROS and the preferred target of ROS attack. Excess ROS can damage mitochondrial components such as DNA, lipids, and proteins, resulting in mitochondrial dysfunction, as manifested by loss of mitochondrial membrane potential and depletion of ATP (Hu and Liu, 2011). Compared to vehicle control cells, 5 and 10 ng/mL T-2 toxin decreased the mitochondrial membrane potential to 60.7% and 41.5% (Fig. 3A and C), while the ATP content decreased to 66.7% and 51.5% (Fig. 3E).
The T-2 toxin is a highly toxic trichothecene mycotoxin that would cause serious toxicity in humans and animals. Recent studies suggest that the central nervous system (CNS) is susceptible to T-2 toxin, which can easily cross the blood-brain barrier, accumulate in brain tissues, and cause neurotoxicity. The growing evidence indicates that oxidative damage and mitochondrial dysfunction play a critical role in T-2 toxin-induced neurotoxicity, but the mechanisms are still poorly understood. Our present study showed that T-2 toxin decreased cell viability and increased lactate dehydrogenase leakage in human neuroblastoma SH-SY5Y cells in a concentration- and time-dependent manner. T-2 toxin elicited prominent oxidative stress and mitochondrial dysfunction, as evidenced by the promotion of cellular reactive oxygen species generation, disruption of the mitochondrial membrane potential, depletion of glutathione and reduction of the cellular ATP content. T-2 toxin impaired mitochondrial biogenesis, including decreased mitochondrial DNA copy number and affected the nuclear factor erythroid 2 related factor 2 (NRF2) / peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α) pathway by upregulating NRF2 mRNA and protein expression while inhibiting the expression of PGC-1α, nuclear respiratory factor (NRF1) and mitochondrial transcription factor A (TFAM). NRF2 knockdown was found to significantly exacerbate T-2 toxin-induced cytotoxicity, oxidative stress, and mitochondrial dysfunction, as well as aggravate mitochondrial biogenesis impairment. NRF2 knockdown compromised T-2 toxin-induced upregulation of NRF2, but augmented the inhibition of PGC-1α, NRF1, and TFAM by T-2 toxin. Taken together, these findings suggest that T-2 toxin-induced oxidative stress and mitochondrial dysfunction in SH-SY5Y cells, at least in part by, NRF2/PGC-1α pathway-mediated mitochondrial biogenesis.
Metformin ameliorates thymus degeneration of mice by regulating mitochondrial function
2022, International Immunopharmacology
As the main lymphoid organ, the thymus degenerates with age. The loss of thymic epithelial cells is mainly related to thymus degeneration and reduced T cells development. As an insulin sensitizer, metformin is a first-line drug for the treatment of diabetes and has been shown to prolong the lifespan of mice, but the mechanism is still unclear. In this study, we explored the therapeutic effect of metformin on thymus degeneration in the accelerated aging mice, which was established by intraperitoneal injection D-galactose (120 mg/kg/day) for eight weeks. Metformin was intragastrically given with 100 or 300 mg/kg body weight per day, respectively, for six weeks. Histological examination showed that metformin administration could alleviate thymus atrophy caused by D-galactose. In addition, metformin therapy increased mitochondrial membrane potential, with a reduction in mitochondrial reactive oxygen species, MDA and SOD levels, and restored mitochondrial balance through enhanced expression of dynamin-related protein 1 (Drp1). Furthermore, metformin altered T lymphocyte subsets and cellular senescent cells; the expression of FoxN1, Aire and Sox2 of thymic epithelial cells also increased. Thus, metformin presented a positive effect on thymic degeneration through improving mitochondrial function. Taken together, these findings revealed an unexpected complexity in the anti-aging of this widely used drug.
Carbon tetrachloride induced mitochondrial division, respiratory chain damage, abnormal intracellular [H<sup>+</sup>] and apoptosis are due to the activation of 5-HT degradation system in hepatocytes
2022, Toxicology and Applied Pharmacology
Citation Excerpt :
Mitochondrial dysfunction is mainly manifested as increased ROS production, decreased ATP synthesis, and cell apoptosis. A study found that ROS, as an inducer (Cohen et al., 1997; Naoi et al., 2009), may trigger mitochondrial dysfunction mainly by interacting with mitochondria and cellular components, such as DNA and proteins (Hu and Liu, 2011; Pieczenik and Neustadt, 2007), which further leads to MMP depolarization and reduced ATP synthesis (Cadenas, 2018). The gene of mitochondrial respiratory chain proteins ND1 and CYTB and a subunit ATP6 of ATP synthase are located in the mitochondria (Kotrys and Szczesny, 2019).
Previously we found that acute liver injury (ALI) with inflammation caused by carbon tetrachloride (CCl₄) was associated with the activation of the 5-HT degradation system (5DS), which includes monoamine oxidase A (MAO-A), the 5-HT_2A receptor, and 5-HT synthases in hepatocytes. This study aimed to determine the role of 5DS in mitochondrial damage and apoptosis. In hepatocyte LO2 cells, CCl₄ activated 5-HT_2A receptor at the gene level, and then 5-HT_2A receptor mediated the expression of 5-HT synthase and MAO-A at the gene level. Suppression of 5DS with the 5-HT_2A receptor antagonist, MAO-A inhibitor, or gene silencing MAO-A significantly reduced the CCl₄-induced production of mitochondrial reactive oxygen species (ROS). The ROS-associated upregulation of mitochondrial division proteins (FIS1 and DRP1); downregulation of mitochondrial fusion-associated protein 1, respiratory chain proteins (ND1 and CYTB), and ATP6; and decrease of ATP levels were reversed. Moreover, ROS-associated abnormal levels of caspase pathway-associated proteins (Bcl-2, Bax, cleaved-caspase3 and cleaved-caspase9) and apoptosis were suppressed. Notably, a combination of 5-HT_2A receptor antagonist and MAO-A inhibitor almost abolished CCl₄ cytotoxicity; abolished mitochondrial membrane potential (MMP) depolarization, mitochondrial structural abnormality, and high mitochondrial pH, with low pH states of the nucleus and cytoplasm. The effects of both were more significant than either alone. LO2 cells exposed to H₂O₂ or depleted mitochondrial ROS showed that ROS induced mitochondrial division and apoptosis and inhibited the levels of respiratory chain proteins. CCl₄-induced abnormalities of ATP generation and MMP were dependent on both ROS and other 5DS-associated factors, probably NH₃. Investigation of CCl₄-induced ALI mice showed that hepatic injury and apoptosis occur at the site of 5DS activation and are significantly inhibited by the 5-HT_2A receptor antagonist and 5-HT synthetic inhibitor in a synergistic manner, as well as mitochondrial damage. Together, we revealed the close relationship between CCl₄-induced activation of 5DS and mitochondrial damage, abnormal intracellular [H⁺], and apoptosis in hepatocytes.
Age-related mitochondrial dysfunction as a key factor in COVID-19 disease
2020, Experimental Gerontology
SARS-CoV-2 causes a severe pneumonia (COVID-19) that affects essentially elderly people. In COVID-19, macrophage infiltration into the lung causes a rapid and intense cytokine storm leading finally to a multi-organ failure and death. Comorbidities such as metabolic syndrome, obesity, type 2 diabetes, lung and cardiovascular diseases, all of them age-associated diseases, increase the severity and lethality of COVID-19. Mitochondrial dysfunction is one of the hallmarks of aging and COVID-19 risk factors. Dysfunctional mitochondria is associated with defective immunological response to viral infections and chronic inflammation. This review discuss how mitochondrial dysfunction is associated with defective immune response in aging and different age-related diseases, and with many of the comorbidities associated with poor prognosis in the progression of COVID-19. We suggest here that chronic inflammation caused by mitochondrial dysfunction is responsible of the explosive release of inflammatory cytokines causing severe pneumonia, multi-organ failure and finally death in COVID-19 patients. Preventive treatments based on therapies improving mitochondrial turnover, dynamics and activity would be essential to protect against COVID-19 severity.

View all citing articles on Scopus

View full text

ReviewMitochondrial stress: A bridge between mitochondrial dysfunction and metabolic diseases?

Abstract

Introduction

Section snippets

Mitochondrial dysfunction is closely associated with metabolic disorders

Quality control system in mitochondria

Mitochondrial stress and unfolded protein response

Cross-talk between mitochondria and ER during stress

Conclusion remarks: Is mitochondrial stress a bridge between mitochondrial dysfunction and insulin resistance?

Child Adolesc Psychiatr Clin N Am

J Mol Cell Cardiol

Curr Biol

Endocrinol Metab Clin North Am

Am J Pathol

Diabetes Metab

Pharmacol Ther

Hepatology

J Hepatol

Am J Pathol

Cell

Free Radic Biol Med

J Biol Chem

J Biol Chem

Mol Cell

Dev Cell

Trends Cell Biol

Gene

J Biol Chem

Cell

Mol Cell

Diabetes Res Clin Pract

J Diabetes Complications

Cell

Int J Biochem Cell Biol

FEBS Lett

J Biol Chem

J Biol Chem

Cell

J Biol Chem

Semin Cell Dev Biol

Mol Cell

Cell Metab

Cell Metab

Nat Clin Pract Cardiovasc Med

Obes Facts

Diabetes

Diabetes Metab

Annu Rev Genet

Endocrine

Circ Res

Nature

Diabetes

Endocrinology

Circulation

Curr Diab Rep

Proc Natl Acad Sci USA

Review
Mitochondrial stress: A bridge between mitochondrial dysfunction and metabolic diseases?