bims-midhyp 2023-06-18 papers

bims-midhyp

Biomed News

on Mitochondrial dysfunction and hypoxia

Issue of 2023‒06‒18
twelve papers selected by
Alia Abukiwan
University of Heidelberg

Nitric oxide regulates mitochondrial biogenesis in plants.
Fluoride-Induced Mitochondrial Dysfunction and Approaches for Its Intervention.
Mitochondria: at the crossroads between mechanobiology and cell metabolism.
Energy substrate metabolism, mitochondrial structure and oxidative stress after cardiac ischemia-reperfusion in mice lacking UCP3.
Hypoxia response protein HRM1 modulates the activity of mitochondrial electron transport chain in Arabidopsis under hypoxic stress.
Brightness and shadows of mitochondrial ROS in the brain.
Systematic Approaches to Study Eclipsed Targeting of Proteins Uncover a New Family of Mitochondrial Proteins.
Heat Shock Protein 70 Is Involved in the Efficiency of Preconditioning with Cyclosporine A in Renal Ischemia Reperfusion Injury by Modulating Mitochondrial Functions.
The mitochondrial uncoupling effects of nitazoxanide enhances cellular autophagy and promotes the clearance of α-synuclein: Potential role of AMPK-JNK pathway.
PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.
Mitochondrial Dysfunction and Apoptosis in Brain Microvascular Endothelial Cells Following Blast Traumatic Brain Injury.
A high-concentrate diet induces mitochondrial dysfunction by activating the MAPK signaling pathway in the mammary gland of dairy cows.

Plant Cell Environ. 2023 Jun 11.

Nitric oxide regulates mitochondrial biogenesis in plants.

Aprajita Kumari, Vemula Chandra Kaladhar, Nidhi Yadav, Pooja Singh, Kishorekumar Reddy, Kapuganti Jagadis Gupta.

  The site of nitric oxide (NO) production in mitochondrial cytochrome c oxidase and the role of NO in mitochondrial biogenesis are not known in plants. By imposing osmotic stress and recovery on Arabidopsis seedlings we investigated the site of NO production and its role in mitochondrial biogenesis. Osmotic stress reduced growth and mitochondrial number while increasing NO production. During the recovery phase the mitochondrial number increased and this increase was higher in wild type and the high NO-producing Pgb1 silencing line in comparison to the NO-deficient nitrate reductase double mutant (nia1/nia2). Application of nitrite stimulated NO production and mitochondrial number in the nia1/nia2 mutant. Osmotic stress induced COX6b- 3 and COA6-L genes encoding subunits of COX. The mutants cox6b-3 and coa6-l were impaired both in NO production and mitochondrial number during stress to recovery suggesting the involvement of these subunits in nitrite-dependent NO production. Transcripts encoding the mitochondrial protein import machinery showed reduced expression in cox6b-3 and coa6-l mutants. Finally, COX6b-3 and COA6-L interacted with the VQ27 motif-containing protein in the presence of NO. The vq27 mutant was impaired in mitochondrial biogenesis. Our results suggest the involvement of COX derived NO in mitochondrial biogenesis.

Keywords:  cytochrome c oxidase; mitochondria; nitrate reductase; nitrite; phytoglobin

DOI:  https://doi.org/10.1111/pce.14637
Biol Trace Elem Res. 2023 Jun 10.

Fluoride-Induced Mitochondrial Dysfunction and Approaches for Its Intervention.

Sachindra Kumar, Smita Shenoy, Ravindra Shantakumar Swamy, V Ravichandiran, Nitesh Kumar.

  Fluoride is present everywhere in nature. The primary way that individuals are exposed to fluoride is by drinking water. It's interesting to note that while low fluoride levels are good for bone and tooth growth, prolonged fluoride exposure is bad for human health. Additionally, preclinical studies link oxidative stress, inflammation, and programmed cell death to fluoride toxicity. Moreover, mitochondria play a crucial role in the production of reactive oxygen species (ROS). On the other hand, little is known about fluoride's impact on mitophagy, biogenesis, and mitochondrial dynamics. These actions control the growth, composition, and organisation of mitochondria, and the purification of mitochondrial DNA helps to inhibit the production of reactive oxygen species and the release of cytochrome c, which enables cells to survive the effects of fluoride poisoning. In this review, we discuss the different pathways involved in mitochondrial toxicity and dysfunction induced by fluoride. For therapeutic approaches, we discussed different phytochemical and pharmacological agents which reduce the toxicity of fluoride via maintained by imbalanced cellular processes, mitochondrial dynamics, and scavenging the ROS.

Keywords:  Antioxidant; Apoptosis; Fluorosis; Mitochondrial dynamics; ROS

DOI:  https://doi.org/10.1007/s12011-023-03720-1
Biol Cell. 2023 Jun 16.

Mitochondria: at the crossroads between mechanobiology and cell metabolism.

Émilie Su, Catherine Villard, Jean-Baptiste Manneville.

  Metabolism and mechanics are two key facets of structural and functional processes in cells, such as growth, proliferation, homeostasis and regeneration. Their reciprocal regulation has been increasingly acknowledged in recent years: external physical and mechanical cues entail metabolic changes, which in return regulate cell mechanosensing and mechanotransduction. Since mitochondria are pivotal regulators of metabolism, we review here the reciprocal links between mitochondrial morphodynamics, mechanics and metabolism. Mitochondria are highly dynamic organelles which sense and integrate mechanical, physical and metabolic cues to adapt their morphology, the organization of their network and their metabolic functions. While some of the links between mitochondrial morphodynamics, mechanics and metabolism are already well established, others are still poorly documented and open new fields of research. First, cell metabolism is known to correlate with mitochondrial morphodynamics. For instance, mitochondrial fission, fusion and cristae remodeling allow the cell to fine-tune its energy production through the contribution of mitochondrial oxidative phosphorylation and cytosolic glycolysis. Second, mechanical cues and alterations in mitochondrial mechanical properties reshape and reorganize the mitochondrial network. Mitochondrial membrane tension emerges as a decisive physical property which regulates mitochondrial morphodynamics. However, the converse link hypothesizing a contribution of morphodynamics to mitochondria mechanics and/or mechanosensitivity has not yet been demonstrated. Third, we highlight that mitochondrial mechanics and metabolism are reciprocally regulated, although little is known about the mechanical adaptation of mitochondria in response to metabolic cues. Deciphering the links between mitochondrial morphodynamics, mechanics and metabolism still presents significant technical and conceptual challenges but is crucial both for a better understanding of mechanobiology and for potential novel therapeutic approaches in diseases such as cancer. This article is protected by copyright. All rights reserved.

Keywords:  Mitochondrial morphodynamics; cancer; cytoskeleton; glycolysis; mechanotransduction; membrane tension; oxidative phosphorylation

DOI:  https://doi.org/10.1111/boc.202300010
Free Radic Biol Med. 2023 Jun 07. pii: S0891-5849(23)00430-6. [Epub ahead of print]

Energy substrate metabolism, mitochondrial structure and oxidative stress after cardiac ischemia-reperfusion in mice lacking UCP3.

Patricia Sánchez-Pérez, Ana Mata, May-Kristin Torp, Elia López-Bernardo, Christina M Heiestad, Jan Magnus Aronsen, Antonio Molina-Iracheta, Luis J Jiménez-Borreguero, Pablo García-Roves, Ana S H Costa, Christian Frezza, Michael P Murphy, Kåre-Olav Stenslokken, Susana Cadenas.

  Myocardial ischemia-reperfusion (IR) injury may result in cardiomyocyte dysfunction. Mitochondria play a critical role in cardiomyocyte recovery after IR injury. The mitochondrial uncoupling protein 3 (UCP3) has been proposed to reduce mitochondrial reactive oxygen species (ROS) production and to facilitate fatty acid oxidation. As both mechanisms might be protective following IR injury, we investigated functional, mitochondrial structural, and metabolic cardiac remodeling in wild-type mice and in mice lacking UCP3 (UCP3-KO) after IR. Results showed that infarct size in isolated perfused hearts subjected to IR ex vivo was larger in adult and old UCP3-KO mice than in equivalent wild-type mice, and was accompanied by higher levels of creatine kinase in the effluent and by more pronounced mitochondrial structural changes. The greater myocardial damage in UCP3-KO hearts was confirmed in vivo after coronary artery occlusion followed by reperfusion. S1QEL, a suppressor of superoxide generation from site IQ in complex I, limited infarct size in UCP3-KO hearts, pointing to exacerbated superoxide production as a possible cause of the damage. Metabolomics analysis of isolated perfused hearts confirmed the reported accumulation of succinate, xanthine and hypoxanthine during ischemia, and a shift to anaerobic glucose utilization, which all recovered upon reoxygenation. The metabolic response to ischemia and IR was similar in UCP3-KO and wild-type hearts, being lipid and energy metabolism the most affected pathways. Fatty acid oxidation and complex I (but not complex II) activity were equally impaired after IR. Overall, our results indicate that UCP3 deficiency promotes enhanced superoxide generation and mitochondrial structural changes that increase the vulnerability of the myocardium to IR injury.

Keywords:  Energy metabolism; Ischemia-reperfusion injury; Mitochondrial respiration; Mitochondrial structure; Oxidative stress; UCP3 (uncoupling protein 3)

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.05.014
New Phytol. 2023 Jun 10.

Hypoxia response protein HRM1 modulates the activity of mitochondrial electron transport chain in Arabidopsis under hypoxic stress.

Kuen-Jin Tsai, Der-Fen Suen, Ming-Che Shih.

  We studied Arabidopsis HYPOXIA-RESPONSIVE MODULATOR 1 (HRM1), which belongs to a group of core hypoxia-responsive genes that are conserved among plant species across great evolutionary distance. The hrm1 mutants had lower survival rates and showed more damage than the wild-type (WT) plants under hypoxic stress. Promoter analyses showed that HRM1 is regulated by EIN3 and RAP2.2 during hypoxia. Fluorescence tracing and immunogold labeling assays showed that HRM1 protein was enriched in mitochondria. Co-immunoprecipitation coupled with mass spectrometry and bimolecular fluorescence complementation assays showed that HRM1 associates with the complex-I in mitochondria. Compared with the WT plants, metabolic activities related to the mitochondrial electron transport chain (mETC) were higher in hrm1 mutants during hypoxia. Loss of HRM1 caused de-repression of mETC complex I, II, and IV activities and higher basal and maximum respiration rates under hypoxia. Our results showed that through association with complex-I, HRM1 attenuates mETC activity and modulates the respiratory chain under low oxygen. Compared with the regulatory system in mammalian, adjustment of mitochondrial respiration to low oxygen helps plants decrease reactive oxygen species production and is also critical for the submergence survival.

Keywords:  HRM1; electron transport chain; ethylene; hypoxia; mitochondria

DOI:  https://doi.org/10.1111/nph.19006
Neurobiol Dis. 2023 Jun 13. pii: S0969-9961(23)00214-0. [Epub ahead of print] 106199

Brightness and shadows of mitochondrial ROS in the brain.

Daniel Jimenez-Blasco, Angeles Almeida, Juan P Bolaños.

  Mitochondrial reactive oxygen species (mROS) have been generally considered harmful byproducts wanted to clear when elevated to avoid brain damage. However, the abundance of mROS in astrocytes is very high -about one order of magnitude above that in neurons-, despite they are essential to preserve cell metabolism and animal behavior. Here, we have focused on this apparent ambiguity by discussing (i) the intrinsic mechanisms accounting for the higher production of mROS by the mitochondrial respiratory chain in astrocytes than in neurons, (ii) the specific molecular targets of astrocytic beneficial mROS, and (iii) how decreased astrocytic mROS causes excess neuronal mROS leading to cellular and organismal damage. We hope that this mini-review serves to clarifying the apparent controversy on the beneficial versus deleterious faces of ROS in the brain from molecular to higher-order organismal levels.

Keywords:  Astrocytes; Glutathione; Mitochondria; Neurons; Reactive oxygen species; Supercomplexes

DOI:  https://doi.org/10.1016/j.nbd.2023.106199
Cells. 2023 Jun 05. pii: 1550. [Epub ahead of print]12(11):

Systematic Approaches to Study Eclipsed Targeting of Proteins Uncover a New Family of Mitochondrial Proteins.

Maayan Mark, Ofir Klein, Yu Zhang, Koyeli Das, Adi Elbaz, Reut Noa Hazan, Michal Lichtenstein, Norbert Lehming, Maya Schuldiner, Ophry Pines.

  Dual localization or dual targeting refers to the phenomenon by which identical, or almost identical, proteins are localized to two (or more) separate compartments of the cell. From previous work in the field, we had estimated that a third of the mitochondrial proteome is dual-targeted to extra-mitochondrial locations and suggested that this abundant dual targeting presents an evolutionary advantage. Here, we set out to study how many additional proteins whose main activity is outside mitochondria are also localized, albeit at low levels, to mitochondria (eclipsed). To do this, we employed two complementary approaches utilizing the α-complementation assay in yeast to uncover the extent of such an eclipsed distribution: one systematic and unbiased and the other based on mitochondrial targeting signal (MTS) predictions. Using these approaches, we suggest 280 new eclipsed distributed protein candidates. Interestingly, these proteins are enriched for distinctive properties compared to their exclusively mitochondrial-targeted counterparts. We focus on one unexpected eclipsed protein family of the Triose-phosphate DeHydrogenases (TDH) and prove that, indeed, their eclipsed distribution in mitochondria is important for mitochondrial activity. Our work provides a paradigm of deliberate eclipsed mitochondrial localization, targeting and function, and should expand our understanding of mitochondrial function in health and disease.

Keywords:  TDH2; TDH3; dual protein targeting; eclipsed protein targeting; mitochondria; yeast model system

DOI:  https://doi.org/10.3390/cells12111550
Int J Mol Sci. 2023 May 31. pii: 9541. [Epub ahead of print]24(11):

Heat Shock Protein 70 Is Involved in the Efficiency of Preconditioning with Cyclosporine A in Renal Ischemia Reperfusion Injury by Modulating Mitochondrial Functions.

Maxime Schleef, Margaux Rozes, Bruno Pillot, Gabriel Bidaux, Fitsum Guebre-Egziabher, Laurent Juillard, Delphine Baetz, Sandrine Lemoine.

  Cyclosporine A (CsA) preconditioning is known to target mitochondrial permeability transition pore and protect renal function after ischemia reperfusion (IR). The upregulation of heat-shock protein 70 (Hsp70) expression after CsA injection is thought to be associated with renal protection. The aim of this study was to test the effect of Hsp70 expression on kidney and mitochondria functions after IR. Mice underwent a right unilateral nephrectomy and 30 min of left renal artery clamping, performed after CsA injection and/or administration of the Hsp70 inhibitor. Histological score, plasma creatinine, mitochondrial calcium retention capacity, and oxidative phosphorylation were assessed after 24 h of reperfusion. In parallel, we used a model of hypoxia reoxygenation on HK2 cells to modulate Hsp70 expression using an SiRNA or a plasmid. We assessed cell death after 18 h of hypoxia and 4 h of reoxygenation. CsA significantly improved renal function, histological score, and mitochondrial functions compared to the ischemic group but the inhibition of Hsp70 repealed the protection afforded by CsA injection. In vitro, Hsp70 inhibition by SiRNA increased cell death. Conversely, Hsp70 overexpression protected cells from the hypoxic condition, as well as the CsA injection. We did not find a synergic association between Hsp70 expression and CsA use. We demonstrated Hsp70 could modulate mitochondrial functions to protect kidneys from IR. This pathway may be targeted by drugs to provide new therapeutics to improve renal function after IR.

Keywords:  Hsp70; cyclosporine A; mitochondria; mitochondrial permeability transition pore; preconditioning; renal ischemia reperfusion

DOI:  https://doi.org/10.3390/ijms24119541
Cell Signal. 2023 Jun 12. pii: S0898-6568(23)00183-3. [Epub ahead of print] 110769

The mitochondrial uncoupling effects of nitazoxanide enhances cellular autophagy and promotes the clearance of α-synuclein: Potential role of AMPK-JNK pathway.

Niharika Amireddy, Vandana Dulam, Shweta Kaul, Rajeswari Pakkiri, Shasi V Kalivendi.

  Upregulation and aggregation of the pre-synaptic protein, α-synuclein plays a key role in Parkinson's disease (PD) and mitochondrial dysfunction was surmised to be an upstream event in the disease pathogenesis. Emerging reports identified the role of nitazoxanide (NTZ), an anti-helminth drug, in enhancing mitochondrial oxygen consumption rate (OCR) and autophagy. In the present study, we have examined the mitochondrial effects of NTZ in mediating cellular autophagy and subsequent clearance of both endogenous and pre-formed aggregates of α-synuclein in cellular model of PD. Our results demonstrate that the mitochondrial uncoupling effects of NTZ results in the activation of AMPK and JNK, which in-turn leads to the enhancement of cellular autophagy. Also,1-methyl-4-phenylpyridinium (MPP+) mediated decrease in autophagic flux with a concomitant increase in the α-synuclein levels were ameliorated in cells treated with NTZ. However, in cells lacking functional mitochondria (ρ0 cells), NTZ did not mitigate MPP+ mediated alterations in the autophagic clearance of α-synuclein, indicating that the mitochondrial effects of NTZ play a crucial role in the clearance of α-synuclein by autophagy. Also, the ability of AMPK inhibitor, compound C, in abrogating NTZ mediated enhancement in the autophagic flux and α-synuclein clearance highlight the pivotal role of AMPK in NTZ mediated autophagy. Further, NTZ per se enhanced the clearance of preformed α-synuclein aggregates that were exogenously added to the cells. Overall, the results of our present study suggest that NTZ activates macroautophagy in cells due to its uncoupling effects on mitochondrial respiration via activation of AMPK-JNK pathway resulting in the clearance of both endogenous and pre-formed α-synuclein aggregates. As NTZ happens to possess good bioavailability and safety profile, considering this drug for PD based on its mitochondrial uncoupling and autophagy enhancing properties for mitigating mitochondrial reactive oxygen species (ROS) and α-synuclein toxicity appears to be a promising therapeutic option.

Keywords:  Autophagy; Mitochondria; Nitazoxanide; Protein aggregation; Uncoupler; α-Synuclein

DOI:  https://doi.org/10.1016/j.cellsig.2023.110769
EMBO J. 2023 Jun 12. e113908

PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.

Valerie Perea, Christian Cole, Justine Lebeau, Vivian Dolina, Kelsey R Baron, Aparajita Madhavan, Jeffery W Kelly, Danielle A Grotjahn, R Luke Wiseman.

  Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are linked in the onset and pathogenesis of numerous diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria during ER stress. The PERK signaling arm of the unfolded protein response (UPR) has emerged as a prominent ER stress-responsive signaling pathway that regulates diverse aspects of mitochondrial biology. Here, we show that PERK activity promotes adaptive remodeling of mitochondrial membrane phosphatidic acid (PA) to induce protective mitochondrial elongation during acute ER stress. We find that PERK activity is required for ER stress-dependent increases in both cellular PA and YME1L-dependent degradation of the intramitochondrial PA transporter PRELID1. These two processes lead to the accumulation of PA on the outer mitochondrial membrane where it can induce mitochondrial elongation by inhibiting mitochondrial fission. Our results establish a new role for PERK in the adaptive remodeling of mitochondrial phospholipids and demonstrate that PERK-dependent PA regulation adapts organellar shape in response to ER stress.

Keywords:  endoplasmic reticulum (ER) stress; mitochondrial morphology; phosphatidic acid; unfolded protein response (UPR)

DOI:  https://doi.org/10.15252/embj.2023113908
Cell Mol Neurobiol. 2023 Jun 14.

Mitochondrial Dysfunction and Apoptosis in Brain Microvascular Endothelial Cells Following Blast Traumatic Brain Injury.

Rebecca Schmitt, Sana Qayum, Artem Pliss, Andrey N Kuzmin, Vijaya Prakash Krishnan Muthaiah, Kathiravan Kaliyappan, Paras N Prasad, Supriya D Mahajan.

  Blood brain barrier (BBB) breakdown is a key driver of traumatic brain injury (TBI), contributing to prolonged neurological deficits and increased risk of death in TBI patients. Strikingly, the role of endothelium in the progression of BBB breakdown has not been sufficiently investigated, even though it constitutes the bulk of BBB structure. In the current study, we investigate TBI-induced changes in the brain endothelium at the subcellular level, particularly focusing on mitochondrial dysfunction, using a combination of confocal imaging, gene expression analysis, and molecular profiling by Raman spectrometry. Herein, we developed and applied an in-vitro blast-TBI (bTBI) model that employs an acoustic shock tube to deliver injury to cultured human brain microvascular endothelial cells (HBMVEC). We found that this injury results in aberrant expression of mitochondrial genes, as well as cytokines/ inflammasomes, and regulators of apoptosis. Furthermore, injured cells exhibit a significant increase in reactive oxygen species (ROS) and in Ca2+ levels. These changes are accompanied by overall reduction of intracellular proteins levels as well as profound transformations in mitochondrial proteome and lipidome. Finally, blast injury leads to a reduction in HBMVEC cell viability, with up to 50% of cells exhibiting signs of apoptosis following 24 h after injury. These findings led us to hypothesize that mitochondrial dysfunction in HBMVEC is a key component of BBB breakdown and TBI progression.

Keywords:  Apoptosis; BBB; Brain Endothelium; Mitochondria; Raman Spectrometry; TBI

DOI:  https://doi.org/10.1007/s10571-023-01372-2
J Dairy Sci. 2023 Jun 07. pii: S0022-0302(23)00330-2. [Epub ahead of print]

A high-concentrate diet induces mitochondrial dysfunction by activating the MAPK signaling pathway in the mammary gland of dairy cows.

Meijuan Meng, Xuerui Li, Ran Huo, Nana Ma, Guangjun Chang, Xiangzhen Shen.

  Subacute rumen acidosis can lead to mastitis in dairy cows. Mitochondrial dysfunction is closely related to the inflammatory response. This experiment was conducted to investigate the effects of a high-concentrate diet on mammary gland inflammation and mitochondrial damage in dairy cows. Twelve Holstein dairy cows in mid-lactation were randomly divided into 2 groups and fed a 40% concentrate (low concentrate, LC) diet or a 60% concentrate (high concentrate, HC) diet. Cows were fed individually, and the experiment lasted for 3 wk. After the experiment, mammary gland tissue, blood, and rumen fluid were collected. Compared with the LC diet, the HC diet significantly decreased rumen pH; the pH was <5.6 for more than 3 h. The HC diet also increased the concentration of LPS in the blood (7.17 ± 1.25 µg/mL vs. 12.12 ± 1.26 µg/mL), which indicated that feeding the HC diet successfully induced subacute rumen acidosis. The HC diet also increased the concentration of Ca2+ (34.80 ± 4.23 µg/g vs. 46.87 ± 7.24 µg/g) in the mammary gland and upregulated the expression of inflammatory factors IL-6 (1,128.31 ± 147.53 pg/g vs. 1,538.42 ± 241.38 pg/g), IL-1β (69.67 ± 5.86 pg/g vs. 90.13 ± 4.78 pg/g), and tumor necrosis factor-α (91.99 ± 10.43 pg/g vs. 131.75 ± 17.89 pg/g) in mammary venous blood. The HC diet also increased the activity of myeloperoxidase (0.41 ± 0.05 U/g vs. 0.71 ± 0.11 U/g) and decreased the content of ATP (0.47 ± 0.10 µg/mL vs. 0.32 ± 0.11 µg/mL) in the mammary gland. In addition, phosphorylation of JNK (1.00 ± 0.21 vs. 2.84 ± 0.75), ERK (1.00 ± 0.20 vs. 1.53 ± 0.31), and p38 (1.00 ± 0.13 vs. 1.47 ± 0.41) and protein expression of IL-6 (1.00 ± 0.22 vs. 2.21 ± 0.27) and IL-8 (1.00 ± 0.17 vs. 1.96 ± 0.26) were enhanced in cows of the HC group, indicating that the mitogen-activated protein kinase (MAPK) signaling pathway was activated. Compared with the LC diet, the HC diet reduced the protein expression of mitochondrial biogenesis-related proteins PGC-1α (1.00 ± 0.17 vs. 0.55 ± 0.12), NRF1 (1.00 ± 0.17 vs. 0.60 ± 0.10), TFAM (1.00 ± 0.10 vs. 0.73 ± 0.09), and SIRTI (1.00 ± 0.44 vs. 0.40 ± 0.10). The HC diet promoted mitochondrial fission and inhibited mitochondrial fusion by reducing protein expression of MFN1 (1.00 ± 0.31 vs. 0.49 ± 0.09), MFN2 (1.00 ± 0.19 vs. 0.69 ± 0.13), and OPA1 (1.00 ± 0.08 vs. 0.72 ± 0.07), and by increasing that of DRP1 (1.00 ± 0.09 vs. 1.39 ± 0.10), MFF (1.00 ± 0.15 vs. 1.89 ± 0.12), and TTC1/FIS1 (1.00 ± 0.08 vs. 1.76 ± 0.14), leading to mitochondrial dysfunction. The HC diet increased mitochondrial permeability by upregulating the protein expression of VDAC1 (1.00 ± 0.42 vs. 1.90 ± 0.44), ANT (1.00 ± 0.22 vs. 1.27 ± 0.17), and CYPD (1.00 ± 0.41 vs. 1.82 ± 0.43). Taken together, these results indicated that feeding the HC diet induced mitochondrial damage via the MAPK signaling pathway in the mammary gland of dairy cows.

Keywords:  high-concentrate diet; mammary gland; mitochondria; mitogen-activated protein kinase (MAPK)

DOI:  https://doi.org/10.3168/jds.2022-22907