scholarly journals Excessively Enlarged Mitochondria in the Kidneys of Diabetic Nephropathy

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 741
Author(s):  
Kiyoung Kim ◽  
Eun-Young Lee
Keyword(s):  
Diabetic Nephropathy ◽  
Mitochondrial Function ◽  
Kidney Failure ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Experimental Models ◽  
Therapeutic Application ◽  
Pathogenic Mechanisms ◽  
Patients With Diabetes ◽  
Molecular Aspects

Diabetic nephropathy (DN) is the most serious complication of diabetes and a leading cause of kidney failure and mortality in patients with diabetes. However, the exact pathogenic mechanisms involved are poorly understood. Impaired mitochondrial function and accumulation of damaged mitochondria due to increased imbalance in mitochondrial dynamics are known to be involved in the development and progression of DN. Accumulating evidence suggests that aberrant mitochondrial fission is involved in the progression of DN. Conversely, studies linking excessively enlarged mitochondria to DN pathogenesis are emerging. In this review, we summarize the current concepts of imbalanced mitochondrial dynamics and their molecular aspects in various experimental models of DN. We discuss the recent evidence of enlarged mitochondria in the kidneys of DN and examine the possibility of a therapeutic application targeting mitochondrial dynamics in DN.

Differential temporal inhibition of mitochondrial fission by Mdivi-1 exerts effective cardioprotection in cardiac ischemia/reperfusion injury

2018 ◽  
Vol 132 (15) ◽  
pp. 1669-1683 ◽  
Author(s):  
Chayodom Maneechote ◽  
Siripong Palee ◽  
Sasiwan Kerdphoo ◽  
Thidarat Jaiwongkam ◽  
Siriporn C. Chattipakorn ◽  
...  
Keyword(s):  
Infarct Size ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Lv Function ◽  
Male Wistar Rats ◽  
Group A

Altered cardiac mitochondrial dynamics with excessive fission is a predominant cause of cardiac dysfunction during ischemia/reperfusion (I/R) injury. Although pre-ischemic inhibition of mitochondrial fission has been shown to improve cardiac function in I/R injury, the effects of this inhibitor given at different time-points during cardiac I/R injury are unknown. Fifty male Wistar rats were subjected to sham and cardiac I/R injury. For cardiac I/R injury, rats were randomly divided into pre-ischemia, during-ischemia, and upon onset of reperfusion group. A mitochondrial fission inhibitor, Mdivi-1 (mitochondrial division inhibitor 1) (1.2 mg/kg) was used. During I/R protocols, the left ventricular (LV) function, arrhythmia score, and mortality rate were determined. Then, the heart was removed to determine infarct size, mitochondrial function, mitochondrial dynamics, and apoptosis. Our results showed that Mdivi-1 given prior to ischemia, exerted the highest level of cardioprotection quantitated through the attenuated incidence of arrhythmia, reduced infarct size, improved cardiac mitochondrial function and fragmentation, and decreased cardiac apoptosis, leading to preserved LV function during I/R injury. Mdivi-1 administered during ischemia and upon the onset of reperfusion also improved cardiac mitochondrial function and LV function, but at a lower efficacy than when it was given prior to ischemia. Taken together, mitochondrial fission inhibition after myocardial ischemic insults still exerts cardioprotection by attenuating mitochondrial dysfunction and dynamic imbalance, leading to decreased infarct size and ultimately improved LV function after acute cardiac I/R injury in rats. These findings indicate its potential clinical usefulness.

scholarly journals Listeria monocytogenes Exploits Mitochondrial Contact Site and Cristae Organizing System Complex Subunit Mic10 To Promote Mitochondrial Fragmentation and Cellular Infection

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Filipe Carvalho ◽  
Anna Spier ◽  
Thibault Chaze ◽  
Mariette Matondo ◽  
Pascale Cossart ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Mitochondrial Function ◽  
Pathogenic Bacteria ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Host Cells ◽  
Mitochondrial Network ◽  
Contact Site ◽  
Content Type ◽  
Cell Functions

ABSTRACT Mitochondrial function adapts to cellular demands and is affected by the ability of the organelle to undergo fusion and fission in response to physiological and nonphysiological cues. We previously showed that infection with the human bacterial pathogen Listeria monocytogenes elicits transient mitochondrial fission and a drop in mitochondrion-dependent energy production through a mechanism requiring the bacterial pore-forming toxin listeriolysin O (LLO). Here, we performed quantitative mitochondrial proteomics to search for host factors involved in L. monocytogenes-induced mitochondrial fission. We found that Mic10, a critical component of the mitochondrial contact site and cristae organizing system (MICOS) complex, is significantly enriched in mitochondria isolated from cells infected with wild-type but not with LLO-deficient L. monocytogenes. Increased mitochondrial Mic10 levels did not correlate with upregulated transcription, suggesting a posttranscriptional mechanism. We then showed that Mic10 is necessary for L. monocytogenes-induced mitochondrial network fragmentation and that it contributes to L. monocytogenes cellular infection independently of MICOS proteins Mic13, Mic26, and Mic27. In conclusion, investigation of L. monocytogenes infection allowed us to uncover a role for Mic10 in mitochondrial fission. IMPORTANCE Pathogenic bacteria can target host cell organelles to take control of key cellular processes and promote their intracellular survival, growth, and persistence. Mitochondria are essential, highly dynamic organelles with pivotal roles in a wide variety of cell functions. Mitochondrial dynamics and function are intimately linked. Our previous research showed that Listeria monocytogenes infection impairs mitochondrial function and triggers fission of the mitochondrial network at an early infection stage, in a process that is independent of the presence of the main mitochondrial fission protein Drp1. Here, we analyzed how mitochondrial proteins change in response to L. monocytogenes infection and found that infection raises the levels of Mic10, a mitochondrial inner membrane protein involved in formation of cristae. We show that Mic10 is important for L. monocytogenes-dependent mitochondrial fission and infection of host cells. Our findings thus offer new insight into the mechanisms used by L. monocytogenes to hijack mitochondria to optimize host infection.

scholarly journals Effect of electrical stimulation-induced resistance exercise on mitochondrial fission and fusion proteins in rat skeletal muscle

2015 ◽  
Vol 40 (11) ◽  
pp. 1137-1142 ◽  
Author(s):  
Yu Kitaoka ◽  
Riki Ogasawara ◽  
Yuki Tamura ◽  
Satoshi Fujita ◽  
Hideo Hatta
Keyword(s):  
Skeletal Muscle ◽  
Electrical Stimulation ◽  
Resistance Exercise ◽  
Mitochondrial Function ◽  
Muscle Protein ◽  
Mitochondrial Dynamics ◽  
Muscle Protein Synthesis ◽  
Mitochondrial Fission ◽  
Dynamic Networks ◽  
Rat Skeletal Muscle

It is well known that resistance exercise increases muscle protein synthesis and muscle strength. However, little is known about the effect of resistance exercise on mitochondrial dynamics, which is coupled with mitochondrial function. In skeletal muscle, mitochondria exist as dynamic networks that are continuously remodeling through fusion and fission. The purpose of this study was to investigate the effect of acute and chronic resistance exercise, which induces muscle hypertrophy, on the expression of proteins related to mitochondrial dynamics in rat skeletal muscle. Resistance exercise consisted of maximum isometric contraction, which was induced by percutaneous electrical stimulation of the gastrocnemius muscle. Our results revealed no change in levels of proteins that regulate mitochondrial fission (Fis1 and Drp1) or fusion (Opa1, Mfn1, and Mfn2) over the 24-h period following acute resistance exercise. Phosphorylation of Drp1 at Ser616 was increased immediately after exercise (P < 0.01). Four weeks of resistance training (3 times/week) increased Mfn1 (P < 0.01), Mfn2 (P < 0.05), and Opa1 (P < 0.01) protein levels without altering mitochondrial oxidative phosphorylation proteins. These observations suggest that resistance exercise has little effect on mitochondrial biogenesis but alters the expression of proteins involved in mitochondrial fusion and fission, which may contribute to mitochondrial quality control and improved mitochondrial function.

scholarly journals Listeria monocytogenes exploits the MICOS complex subunit Mic10 to promote mitochondrial fragmentation and cellular infection

2019 ◽  
Author(s):  
Filipe Carvalho ◽  
Anna Spier ◽  
Thibault Chaze ◽  
Mariette Matondo ◽  
Pascale Cossart ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Mitochondrial Function ◽  
Pathogenic Bacteria ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Host Cells ◽  
Listeriolysin O ◽  
Mitochondrial Network ◽  
Cell Organelles ◽  
Cell Functions

AbstractMitochondrial function adapts to cellular demands and is affected by the ability of the organelle to undergo fusion and fission in response to physiological and non-physiological cues. We previously showed that infection with the human bacterial pathogen Listeria monocytogenes elicits transient mitochondrial fission and a drop in mitochondrial-dependent energy production through a mechanism requiring the bacterial pore-forming toxin listeriolysin O (LLO). Here, we performed quantitative mitochondrial proteomics to search for host factors involved in L. monocytogenes-induced mitochondrial fission. We found that Mic10, a critical component of the mitochondrial contact site and cristae organizing system (MICOS) complex, is significantly enriched in mitochondria isolated from cells infected with wild-type but not with LLO-deficient L. monocytogenes. Increased mitochondrial Mic10 levels did not correlate with upregulated transcription, suggesting a post-transcriptional regulation. We showed that Mic10 is necessary for L. monocytogenes-induced mitochondrial network fragmentation, and that it contributes to L. monocytogenes cellular infection independently of MICOS proteins Mic13, Mic26 and Mic27. Together, L. monocytogenes infection allowed us to uncover a role for Mic10 in mitochondrial fission.ImportancePathogenic bacteria can target host cell organelles to take control of key cellular processes and promote their intracellular survival, growth, and persistence. Mitochondria are essential, highly dynamic organelles with pivotal roles in a wide variety of cell functions. Mitochondrial dynamics and function are intimately linked. Our previous research showed that Listeria monocytogenes infection impairs mitochondrial function and triggers fission of the mitochondrial network at an early infection stage, in a process that is independent of the main mitochondrial fission protein Drp1. Here, we analyzed how mitochondrial proteins change in response to L. monocytogenes infection and found that infection raises the levels of Mic10, a mitochondrial inner membrane protein involved in formation of cristae. We show that Mic10 is important for L. monocytogenes-dependent mitochondrial fission and infection of host cells. Our findings thus offer new insight into the mechanisms used by L. monocytogenes to hijack mitochondria to optimize host infection.

scholarly journals Podocyte bioenergetics in the development of diabetic nephropathy: the role of mitochondria

Endocrinology ◽  
2021 ◽  
Author(s):  
Irena Audzeyenka ◽  
Agnieszka Bierżyńska ◽  
Abigail C Lay
Keyword(s):  
Diabetic Nephropathy ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Signalling Pathways ◽  
Cell Type ◽  
Cellular Functions ◽  
Podocyte Injury ◽  
Underlying Pathogenesis ◽  
Novel Therapeutic

Abstract Diabetic Nephropathy (DN) is the leading cause of kidney failure, with an increasing incidence worldwide. Mitochondrial dysfunction is known to occur in DN and has been implicated in the underlying pathogenesis of disease. These complex organelles have an array of important cellular functions and involvement in signalling pathways; and understanding the intricacies of these responses in health, as well as how they are damaged in disease, is likely to highlight novel therapeutic avenues. A key cell type damaged early in DN is the podocyte and increasing studies have focused on investigating the role of mitochondria in podocyte injury. This review will summarise what is known about podocyte mitochondrial dynamics in DN, with a particular focus on bioenergetic pathways, highlighting key studies in this field and potential opportunities to target, enhance or protect podocyte mitochondrial function in the treatment of DN.

scholarly journals Mitochondrial Dynamics and VMP1-Related Selective Mitophagy in Experimental Acute Pancreatitis

2021 ◽  
Vol 9 ◽  
Author(s):  
Virginia Vanasco ◽  
Alejandro Ropolo ◽  
Daniel Grasso ◽  
Diego S. Ojeda ◽  
María Noé García ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Cell Model ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Pancreatic Acinar Cells ◽  
Atp Production ◽  
Selective Autophagy ◽  
Mild Disease

Mitophagy and zymophagy are selective autophagy pathways early induced in acute pancreatitis that may explain the mild, auto limited, and more frequent clinical presentation of this disease. Adequate mitochondrial bioenergetics is necessary for cellular restoration mechanisms that are triggered during the mild disease. However, mitochondria and zymogen contents are direct targets of damage in acute pancreatitis. Cellular survival depends on the recovering possibility of mitochondrial function and efficient clearance of damaged mitochondria. This work aimed to analyze mitochondrial dynamics and function during selective autophagy in pancreatic acinar cells during mild experimental pancreatitis in rats. Also, using a cell model under the hyperstimulation of the G-coupled receptor for CCK (CCK-R), we aimed to investigate the mechanisms involved in these processes in the context of zymophagy. We found that during acute pancreatitis, mitochondrial O2consumption and ATP production significantly decreased early after induction of acute pancreatitis, with a consequent decrease in the ATP/O ratio. Mitochondrial dysfunction was accompanied by changes in mitochondrial dynamics evidenced by optic atrophy 1 (OPA-1) and dynamin-related protein 1 (DRP-1) differential expression and ultrastructural features of mitochondrial fission, mitochondrial elongation, and mitophagy during the acute phase of experimental mild pancreatitis in rats. Mitophagy was also evaluated by confocal assay after transfection with the pMITO-RFP-GFP plasmid that specifically labels autophagic degradation of mitochondria and the expression and redistribution of the ubiquitin ligase Parkin1. Moreover, we report for the first time that vacuole membrane protein-1 (VMP1) is involved and required in the mitophagy process during acute pancreatitis, observable not only by repositioning around specific mitochondrial populations, but also by detection of mitochondria in autophagosomes specifically isolated with anti-VMP1 antibodies as well. Also, VMP1 downregulation avoided mitochondrial degradation confirming that VMP1 expression is required for mitophagy during acute pancreatitis. In conclusion, we identified a novel DRP1-Parkin1-VMP1 selective autophagy pathway, which mediates the selective degradation of damaged mitochondria by mitophagy in acute pancreatitis. The understanding of the molecular mechanisms involved to restore mitochondrial function, such as mitochondrial dynamics and mitophagy, could be relevant in the development of novel therapeutic strategies in acute pancreatitis.

scholarly journals MiR-195 regulates mitochondrial function by targeting mitofusin-2 in breast cancer cells

2018 ◽  
Author(s):  
Paresh Kumar Purohit ◽  
Ruairidh Edwards ◽  
Kostas Tokatlidis ◽  
Neeru Saini
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Mitochondrial Function ◽  
Breast Cancer Cells ◽  
Therapeutic Potential ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitofusin 2 ◽  
Er Positive ◽  
And Function

AbstractMitochondrial dynamics is a highly dysregulated process in cancer. Apoptosis and mitochondrial fission are two concurrent events wherein increased mitochondrial fragmentation serves as a hallmark of apoptosis. We have shown earlier that miR-195 exerts pro-apoptotic effects in breast cancer cells. Herein, we have demonstrated miR-195 as a modulator of mitochondrial dynamics and function. Imaging experiments upon miR-195 treatment have shown that mitochondria undergo extensive fission. We validated mitofusin2 as a potential target of miR-195. Which may provide a molecular explanation for the respiratory defects induced by miR-195 over-expression in breast cancer cells? Active, but not total, mitochondrial mass, was reduced with increasing levels of miR-195. We have further shown that miR-195 enhances mitochondrial SOD-2 expression but does not affect PINK1 levels in breast cancer cells. Collectively, we have revealed that miR-195 is a modulator of mitochondrial dynamics by targeting MFN2 thereby impairing mitochondrial function. Concomitantly, it enhances the scavenger of reactive oxygen species (SOD-2) to maintain moderate levels of oxidative stress. Our findings suggest a therapeutic potential of miR-195 in both ER-positive as well as ER-negative breast cancer cells.

scholarly journals Dynamin-Related Protein 1 Deficiency Promotes Recovery from AKI

2017 ◽  
Vol 29 (1) ◽  
pp. 194-206 ◽  
Author(s):  
Heather M. Perry ◽  
Liping Huang ◽  
Rebecca J. Wilson ◽  
Amandeep Bajwa ◽  
Hiromi Sesaki ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Kidney Injury ◽  
Related Protein

The proximal tubule epithelium relies on mitochondrial function for energy, rendering the kidney highly susceptible to ischemic AKI. Dynamin-related protein 1 (DRP1), a mediator of mitochondrial fission, regulates mitochondrial function; however, the cell-specific and temporal role of DRP1 in AKI in vivo is unknown. Using genetic murine models, we found that proximal tubule–specific deletion of Drp1 prevented the renal ischemia-reperfusion–induced kidney injury, inflammation, and programmed cell death observed in wild-type mice and promoted epithelial recovery, which associated with activation of the renoprotective β-hydroxybutyrate signaling pathway. Loss of DRP1 preserved mitochondrial structure and reduced oxidative stress in injured kidneys. Lastly, proximal tubule deletion of DRP1 after ischemia-reperfusion injury attenuated progressive kidney injury and fibrosis. These results implicate DRP1 and mitochondrial dynamics as an important mediator of AKI and progression to fibrosis and suggest that DRP1 may serve as a therapeutic target for AKI.

scholarly journals Age-Dependent Decline in Synaptic Mitochondrial Function Is Exacerbated in Vulnerable Brain Regions of Female 3xTg-AD Mice

2020 ◽  
Vol 21 (22) ◽  
pp. 8727
Author(s):  
César Espino de la Fuente-Muñoz ◽  
Mónica Rosas-Lemus ◽  
Perla Moreno-Castilla ◽  
Federico Bermúdez-Rattoni ◽  
Salvador Uribe-Carvajal ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Brain Regions ◽  
Synaptic Function ◽  
Early Event ◽  
Wild Mice ◽  
Ad Mouse Model ◽  
Main Factor

Synaptic aging has been associated with neuronal circuit dysfunction and cognitive decline. Reduced mitochondrial function may be an early event that compromises synaptic integrity and neurotransmission in vulnerable brain regions during physiological and pathological aging. Thus, we aimed to measure mitochondrial function in synapses from three brain regions at two different ages in the 3xTg-AD mouse model and in wild mice. We found that aging is the main factor associated with the decline in synaptic mitochondrial function, particularly in synapses isolated from the cerebellum. Accumulation of toxic compounds, such as tau and Aβ, that occurred in the 3xTg-AD mouse model seemed to participate in the worsening of this decline in the hippocampus. The changes in synaptic bioenergetics were also associated with increased activation of the mitochondrial fission protein Drp1. These results suggest the presence of altered mechanisms of synaptic mitochondrial dynamics and their quality control during aging and in the 3xTg-AD mouse model; they also point to bioenergetic restoration as a useful therapeutic strategy to preserve synaptic function during aging and at the early stages of Alzheimer’s disease (AD).

scholarly journals Deletion of VDAC1 Hinders Recovery of Mitochondrial and Renal Functions After Acute Kidney Injury

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 585 ◽  
Author(s):  
Grazyna Nowak ◽  
Judit Megyesi ◽  
William J. Craigen
Keyword(s):  
Acute Kidney Injury ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Kidney Injury ◽  
Atp Content ◽  
Respiratory Complexes ◽  
Kidney Morphology ◽  
Kidney Functions ◽  
Fof1 Atpase

Voltage-dependent anion channels (VDACs) constitute major transporters mediating bidirectional movement of solutes between cytoplasm and mitochondria. We aimed to determine if VDAC1 plays a role in recovery of mitochondrial and kidney functions after ischemia-induced acute kidney injury (AKI). Kidney function decreased after ischemia and recovered in wild-type (WT), but not in VDAC1-deficient mice. Mitochondrial maximum respiration, activities of respiratory complexes and FoF1-ATPase, and ATP content in renal cortex decreased after ischemia and recovered in WT mice. VDAC1 deletion reduced respiration and ATP content in non-injured kidneys. Further, VDAC1 deletion blocked return of activities of respiratory complexes and FoF1-ATPase, and recovery of respiration and ATP content after ischemia. Deletion of VDAC1 exacerbated ischemia-induced mitochondrial fission, but did not aggravate morphological damage to proximal tubules after ischemia. However, VDAC1 deficiency impaired recovery of kidney morphology and increased renal interstitial collagen accumulation. Thus, our data show a novel role for VDAC1 in regulating renal mitochondrial dynamics and recovery of mitochondrial function and ATP levels after AKI. We conclude that the presence of VDAC1 (1) stimulates capacity of renal mitochondria for respiration and ATP production, (2) reduces mitochondrial fission, (3) promotes recovery of mitochondrial function and dynamics, renal morphology, and kidney functions, and (4) increases survival after AKI.

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