Molecular Biomarkers of the Mitochondrial Quality Control Are Differently Affected by Hypoxia-Reoxygenation Stress in Marine Bivalves Crassostrea gigas and Mytilus edulis

Coastal environments commonly experience strong oxygen fluctuations. Resulting hypoxia/reoxygenation stress can negatively affect mitochondrial functions, since oxygen deficiency impairs ATP generation, whereas a surge of oxygen causes mitochondrial damage by oxidative stress. Marine intertidal bivalves are adapted to fluctuating oxygen conditions, yet the underlying molecular mechanisms that sustain mitochondrial integrity and function during oxygen fluctuations are not yet well understood. We used targeted mRNA expression analysis to determine the potential involvement of the mitochondrial quality control mechanisms in responses to short-term hypoxia (24 h at <0.01% O2) and subsequent reoxygenation (1.5 h at 21% O2) in two hypoxia-tolerant marine bivalves, the Pacific oysters Crassostrea gigas and the blue mussels Mytilus edulis. We hypothesized that the genes involved in the mitochondrial quality control will be upregulated during hypoxia, and the less hypoxia-tolerant of the two studied species (M. edulis) will show a stronger dependence on transcriptional upregulation of these pathways than C. gigas. To test these hypotheses, mRNA expression of 17 (C. gigas) and 11 (M. edulis) marker genes involved in mitochondrial fusion, fission, proteolysis and mitophagy was analyzed in the digestive gland of M. edulis and C. gigas in normoxia and during hypoxia-reoxygenation (H/R) stress. In the mussels, the mRNA expression of the transcripts related to mitochondrial dynamics and quality control was strongly altered during H/R stress showing a shift toward fission, suppression of fusion, an increase in mitochondrial proteolysis and onset of mitophagy. These changes indicate that H/R stress induces mitochondrial injury in M. edulis requiring upregulation of the protective mechanisms to segregate the dysfunctional mitochondria by fission and degrade the oxidative damaged proteins and/or organelles. Unlike mussels, the transcript levels of all studied genes in the oysters remained at the baseline (normoxic) levels during H/R stress. This muted transcriptional response of C. gigas is in agreement with earlier findings showing better ability to maintain cellular homeostasis and higher resistance to apoptosis during H/R stress in the oysters compared with the mussels. The revealed species-specific differences in the expression of the mitochondrial quality control pathways shed light on the potentially important mechanisms of mitochondrial protection against H/R-induced damage that might contribute to hypoxia tolerance in marine bivalves.

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PINK1: A Bridge between Mitochondria and Parkinson’s Disease

Life ◽

10.3390/life11050371 ◽

2021 ◽

Vol 11 (5) ◽

pp. 371

Author(s):

Filipa Barroso Gonçalves ◽

Vanessa Alexandra Morais

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Quality Control ◽

High Energy ◽

Common Denominator ◽

Mitochondrial Quality Control ◽

Mitochondrial Homeostasis ◽

Cellular Environment ◽

Familial Form ◽

Mitochondrial Functions

Mitochondria are known as highly dynamic organelles essential for energy production. Intriguingly, in the recent years, mitochondria have revealed the ability to maintain cell homeostasis and ultimately regulate cell fate. This regulation is achieved by evoking mitochondrial quality control pathways that are capable of sensing the overall status of the cellular environment. In a first instance, actions to maintain a robust pool of mitochondria take place; however, if unsuccessful, measures that lead to overall cell death occur. One of the central key players of these mitochondrial quality control pathways is PINK1 (PTEN-induce putative kinase), a mitochondrial targeted kinase. PINK1 is known to interact with several substrates to regulate mitochondrial functions, and not only is responsible for triggering mitochondrial clearance via mitophagy, but also participates in maintenance of mitochondrial functions and homeostasis, under healthy conditions. Moreover, PINK1 has been associated with the familial form of Parkinson’s disease (PD). Growing evidence has strongly linked mitochondrial homeostasis to the central nervous system (CNS), a system that is replenished with high energy demanding long-lasting neuronal cells. Moreover, sporadic cases of PD have also revealed mitochondrial impairments. Thus, one could speculate that mitochondrial homeostasis is the common denominator in these two forms of the disease, and PINK1 may play a central role in maintaining mitochondrial homeostasis. In this review, we will discuss the role of PINK1 in the mitochondrial physiology and scrutinize its role in the cascade of PD pathology.

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Effects of intermittent hypoxia on cell survival and inflammatory responses in the intertidal marine bivalves Mytilus edulis and Crassostrea gigas

Journal of Experimental Biology ◽

10.1242/jeb.217026 ◽

2020 ◽

Vol 223 (4) ◽

pp. jeb217026 ◽

Cited By ~ 2

Author(s):

Halina Falfushynska ◽

Helen Piontkivska ◽

Inna M. Sokolova

Keyword(s):

Cell Survival ◽

Mytilus Edulis ◽

Crassostrea Gigas ◽

Intermittent Hypoxia ◽

Inflammatory Responses ◽

Marine Bivalves

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Dystrophin deficiency disrupts muscle clock expression and mitochondrial quality control in mdx mice

AJP Cell Physiology ◽

10.1152/ajpcell.00188.2021 ◽

2021 ◽

Author(s):

Justin P. Hardee ◽

Marissa K. Caldow ◽

Audrey S.M. Chan ◽

Stuart K. Plenderleith ◽

Jennifer Trieu ◽

...

Keyword(s):

Quality Control ◽

Mrna Expression ◽

Tibialis Anterior ◽

Oxidative Capacity ◽

Mdx Mice ◽

Dark Cycle ◽

Mitochondrial Quality Control ◽

The Core ◽

Dystrophin Deficiency ◽

Diurnal Regulation

Impaired oxidative capacity and mitochondrial function contribute to the dystrophic pathology in muscles of Duchenne muscular dystrophy (DMD) patients and in relevant mouse models of the disease. Emerging evidence suggests an association between disrupted core clock expression and mitochondrial quality control, but this has not been established in muscles lacking dystrophin. We examined the diurnal regulation of muscle core clock and mitochondrial quality control expression in dystrophin-deficient C57BL/10ScSn-Dmdmdx (mdx) mice, an established model of DMD. Male C57BL/10 (BL/10; n=18) and mdx mice (n=18) were examined every 4 hours beginning at the dark cycle. Throughout the entire light-dark cycle, extensor digitorum longus (EDL) muscles from mdx mice had decreased core clock mRNA expression (Arntl, Cry1, Cry2, Nr1d2; p<0.05) and disrupted mitochondrial quality control mRNA expression related to biogenesis (decreased; Ppargc1a, Esrra; p<0.05), fission (increased; Dnm1l; p<0.01), fusion (decreased; Opa1, Mfn1; p<0.05) and autophagy/mitophagy (decreased: Bnip3; p<0.05; increased: Becn1; p<0.05). Cosinor analysis revealed a decrease in the rhythmicity parameters mesor and amplitude for Arntl, Cry1, Cry2, Per2, and Nr1d1 (p<0.001) in mdx mice. Diurnal oscillations in Esrra, Sirt1, Map1lc3b and Sqstm1 were absent in mdx mice, along with decreased mesor and amplitude of Ppargc1a mRNA expression (p<0.01). The expression of proteins involved in mitochondrial biogenesis (decreased: PPARGC1A, p<0.05) and autophagy/mitophagy (increased: MAP1LC3BII, SQSTM1, BNIP3; p<0.05) were also dysregulated in tibialis anterior muscles of mdx mice. These findings suggest that dystrophin deficiency in mdx mice impairs the regulation of the core clock and mitochondrial quality control, with relevance to DMD and related disorders.

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Comparative Toxicokinetics and Antioxidant Response in the Microcystin-LR-Exposed Gill of Two Marine Bivalves, Crassostrea gigas and Mytilus edulis

Journal of Shellfish Research ◽

10.2983/035.037.0305 ◽

2018 ◽

Vol 37 (3) ◽

pp. 497-506 ◽

Cited By ~ 2

Author(s):

Bo-Mi Kim ◽

MD. Niamul Haque ◽

Do-Hee Lee ◽

Sang-Eun Nam ◽

Jae-Sung Rhee

Keyword(s):

Mytilus Edulis ◽

Crassostrea Gigas ◽

Antioxidant Response ◽

Marine Bivalves

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Intracellular vesicle trafficking plays an essential role in mitochondrial quality control

Molecular Biology of the Cell ◽

10.1091/mbc.e17-10-0619 ◽

2018 ◽

Vol 29 (7) ◽

pp. 809-819

Author(s):

Mike Gerards ◽

Giuseppe Cannino ◽

Jose M. González de Cózar ◽

Howard T. Jacobs

Keyword(s):

Quality Control ◽

Live Cell Imaging ◽

Vesicle Trafficking ◽

Cell Diameter ◽

Gene Products ◽

Mitochondrial Quality Control ◽

Proteotoxic Stress ◽

Intracellular Vesicle ◽

Mitochondrial Functions ◽

Tiny Amount

The Drosophila gene products Bet1, Slh, and CG10144, predicted to function in intracellular vesicle trafficking, were previously found to be essential for mitochondrial nucleoid maintenance. Here we show that Slh and Bet1 cooperate to maintain mitochondrial functions. In their absence, mitochondrial content, membrane potential, and respiration became abnormal, accompanied by mitochondrial proteotoxic stress, but without direct effects on mtDNA. Immunocytochemistry showed that both Slh and Bet1 are localized at the Golgi, together with a proportion of Rab5-positive vesicles. Some Bet1, as well as a tiny amount of Slh, cofractionated with highly purified mitochondria, while live-cell imaging showed coincidence of fluorescently tagged Bet1 with most Lysotracker-positive and a small proportion of Mitotracker-positive structures. This three-way association was disrupted in cells knocked down for Slh, although colocalized lysosomal and mitochondrial signals were still seen. Neither Slh nor Bet1 was required for global mitophagy or endocytosis, but prolonged Slh knockdown resulted in G2 growth arrest, with increased cell diameter. These effects were shared with knockdown of betaCOP but not of CG1044, Snap24, or Syntaxin6. Our findings implicate vesicle sorting at the cis-Golgi in mitochondrial quality control.

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Mitochondrial Mechanisms Underlying Tolerance to Fluctuating Oxygen Conditions: Lessons from Hypoxia-Tolerant Organisms

Integrative and Comparative Biology ◽

10.1093/icb/icz047 ◽

2019 ◽

Vol 59 (4) ◽

pp. 938-952 ◽

Cited By ~ 5

Author(s):

Inna M Sokolova ◽

Eugene P Sokolov ◽

Fouzia Haider

Keyword(s):

Quality Control ◽

Metabolic Regulation ◽

Hypoxia Inducible Factor ◽

Hypoxia Tolerance ◽

Control Mechanisms ◽

Mitochondrial Quality Control ◽

Severe Problem ◽

Terrestrial Vertebrates ◽

Tolerant Species ◽

Tolerance To Hypoxia

Abstract Oxygen (O2) is essential for most metazoan life due to its central role in mitochondrial oxidative phosphorylation (OXPHOS), which generates >90% of the cellular adenosine triphosphate. O2 fluctuations are an ultimate mitochondrial stressor resulting in mitochondrial damage, energy deficiency, and cell death. This work provides an overview of the known and putative mechanisms involved in mitochondrial tolerance to fluctuating O2 conditions in hypoxia-tolerant organisms including aquatic and terrestrial vertebrates and invertebrates. Mechanisms of regulation of the mitochondrial OXPHOS and electron transport system (ETS) (including alternative oxidases), sulphide tolerance, regulation of redox status and mitochondrial quality control, and the potential role of hypoxia-inducible factor (HIF) in mitochondrial tolerance to hypoxia are discussed. Mitochondrial phenotypes of distantly related animal species reveal common features including conservation and/or anticipatory upregulation of ETS capacity, suppression of reactive oxygen species (ROS)-producing electron flux through ubiquinone, reversible suppression of OXPHOS activity, and investment into the mitochondrial quality control mechanisms. Despite the putative importance of oxidative stress in adaptations to hypoxia, establishing the link between hypoxia tolerance and mitochondrial redox mechanisms is complicated by the difficulties of establishing the species-specific concentration thresholds above which the damaging effects of ROS outweigh their potentially adaptive signaling function. The key gaps in our knowledge about the potential mechanisms of mitochondrial tolerance to hypoxia include regulation of mitochondrial biogenesis and fusion/fission dynamics, and HIF-dependent metabolic regulation that require further investigation in hypoxia-tolerant species. Future physiological, molecular and genetic studies of mitochondrial responses to hypoxia, and reoxygenation in phylogenetically diverse hypoxia-tolerant species could reveal novel solutions to the ubiquitous and metabolically severe problem of O2 deficiency and would have important implications for understanding the evolution of hypoxia tolerance and the potential mitigation of pathological states caused by O2 fluctuations.

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Vanadium Induces Oxidative Stress and Mitochondrial Quality Control Disorder in the Heart of Ducks

Frontiers in Veterinary Science ◽

10.3389/fvets.2021.756534 ◽

2021 ◽

Vol 8 ◽

Author(s):

Zhiwei Xiong ◽

Chenghong Xing ◽

Tianfang Xu ◽

Yan Yang ◽

Guohui Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Quality Control ◽

Mitochondrial Fission ◽

Control Group ◽

Mrna Levels ◽

Mitochondrial Quality Control ◽

Related Factors ◽

Sod Activity ◽

Vacuolar Degeneration ◽

Mitochondrial Functions

Vanadium (V) is an ultra-trace element presenting in humans and animals, but excessive V can cause toxic effects. Mitochondrial quality control (MQC) is an essential process for maintaining mitochondrial functions, but the relationship between V toxicity and MQC is unclear. To investigate the effects of excessive V on oxidative stress and MQC in duck hearts, 72 ducks were randomly divided into two groups, including the control group and the V group (30 mg of V/kg dry matter). The cardiac tissues were collected for the histomorphology observation and oxidative stress status evaluation at 22 and 44 days. In addition, the mRNA and protein levels of MQC-related factors were also analyzed. The results showed that excessive V could trigger vacuolar degeneration, granular degeneration, as well as mitochondrial vacuolization and swelling in myocardial cells. In addition, CAT activity was elevated in two time points, while T-SOD activity was increased in 22 days but decreased in 44 days after V treatment. Meanwhile, excessive V intake could also increase the number of Drp1 puncta, the mRNA levels of mitochondrial fission–related factors (Drp1and MFF), and protein (MFF) level, but decrease the number of Parkin puncta and the mitochondrial biogenesis (PGC-1α, NRF-1, and TFAM), mitochondrial fusion (OPA1, Mfn1, and Mfn2), and mitophagy (Parkin, PINK1, P62, and LC3B) related mRNA levels and protein (PGC-1α, Mfn1, Mfn2, PINK1) levels. Collectively, our results suggested that excessive V could induce oxidative stress and MQC disorder in the heart of ducks.

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Trimetazidine and exercise provide comparable improvements to high fat diet-induced muscle dysfunction through enhancement of mitochondrial quality control

Scientific Reports ◽

10.1038/s41598-021-98771-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Wenliang Zhang ◽

Baiyang You ◽

Dake Qi ◽

Ling Qiu ◽

Jeffrey W. Ripley-Gonzalez ◽

...

Keyword(s):

Skeletal Muscle ◽

Quality Control ◽

Mitochondrial Dysfunction ◽

Muscle Atrophy ◽

High Fat Diet ◽

C2c12 Cells ◽

Muscle Dysfunction ◽

High Fat ◽

Mitochondrial Quality Control ◽

Mitochondrial Functions

AbstractObesity induces skeletal muscle dysfunction. The pathogenesis of which appears to substantially involve mitochondrial dysfunction, arising from impaired quality control. Exercise is a major therapeutic strategy against muscle dysfunction. Trimetazidine, a partial inhibitor of lipid oxidation, has been proposed as a metabolic modulator for several cardiovascular pathologies. However, the effects of Trimetazidine on regulating skeletal muscle function are largely unknown. Our present study used cell culture and obese mice models to test a novel hypothesis that Trimetazidine could improve muscle atrophy with similar results to exercise. In C2C12 cells, high palmitic acid-induced atrophy and mitochondrial dysfunction, which could be reversed by the treatment of Trimetazidine. In our animal models, with high-fat diet-induced obesity associated with skeletal muscle atrophy, Trimetazidine prevented muscle dysfunction, corrected metabolic abnormalities, and improved mitochondrial quality control and mitochondrial functions similarly to exercise. Thus, our study suggests that Trimetazidine successfully mimics exercise to enhance mitochondrial quality control leading to improved high-fat diet-induced muscle dysfunction.

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