bims-ecasc1 2024-10-06 papers

Issue of 2024‒10‒06
four papers selected by
Bill Suzor, Cure Mito Foundation

Int J Mol Sci. 2024 Sep 16. pii: 9975. [Epub ahead of print]25(18):

New Insights into Mitochondria in Health and Diseases.

Ya Li, Huhu Zhang, Chunjuan Yu, Xiaolei Dong, Fanghao Yang, Mengjun Wang, Ziyuan Wen, Mohan Su, Bing Li, Lina Yang.

Mitochondria are a unique type of semi-autonomous organelle within the cell that carry out essential functions crucial for the cell's survival and well-being. They are the location where eukaryotic cells carry out energy metabolism. Aside from producing the majority of ATP through oxidative phosphorylation, which provides essential energy for cellular functions, mitochondria also participate in other metabolic processes within the cell, such as the electron transport chain, citric acid cycle, and β-oxidation of fatty acids. Furthermore, mitochondria regulate the production and elimination of ROS, the synthesis of nucleotides and amino acids, the balance of calcium ions, and the process of cell death. Therefore, it is widely accepted that mitochondrial dysfunction is a factor that causes or contributes to the development and advancement of various diseases. These include common systemic diseases, such as aging, diabetes, Parkinson's disease, and cancer, as well as rare metabolic disorders, like Kearns-Sayre syndrome, Leigh disease, and mitochondrial myopathy. This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities. Additionally, it provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health.

Keywords: ROS; aging; bioenergetics; mitochondrial; mitochondrial dysfunction; mitochondrial targeted therapy; mtDNA; mutations

DOI: https://doi.org/10.3390/ijms25189975

Genes (Basel). 2024 Sep 01. pii: 1153. [Epub ahead of print]15(9):

Mitochondrial Dysfunctions: Genetic and Cellular Implications Revealed by Various Model Organisms.

Monika Stańczyk, Natalia Szubart, Roman Maslanka, Renata Zadrag-Tecza.

Mitochondria play a crucial role in maintaining the energy status and redox homeostasis of eukaryotic cells. They are responsible for the metabolic efficiency of cells, providing both ATP and intermediate metabolic products. They also regulate cell survival and death under stress conditions by controlling the cell response or activating the apoptosis process. This functional diversity of mitochondria indicates their great importance for cellular metabolism. Hence, dysfunctions of these structures are increasingly recognized as an element of the etiology of many human diseases and, therefore, an extremely promising therapeutic target. Mitochondrial dysfunctions can be caused by mutations in both nuclear and mitochondrial DNA, as well as by stress factors or replication errors. Progress in knowledge about the biology of mitochondria, as well as the consequences for the efficiency of the entire organism resulting from the dysfunction of these structures, is achieved through the use of model organisms. They are an invaluable tool for analyzing complex cellular processes, leading to a better understanding of diseases caused by mitochondrial dysfunction. In this work, we review the most commonly used model organisms, discussing both their advantages and limitations in modeling fundamental mitochondrial processes or mitochondrial diseases.

Keywords: mitochondria; mitochondrial dysfunction; model organisms

DOI: https://doi.org/10.3390/genes15091153

BMC Pediatr. 2024 Sep 28. 24(1): 603

Classic ketogenic diet-induced ketoacidosis in the treatment of pyruvate dehydrogenase deficiency: a case report and literature review.

Rongrong Li, Mingsheng Ma, Wei Chen, Zhengqing Qiu.

BACKGROUND: As a rare mitochondrial disorder, the pyruvate dehydrogenase complex (PDC) deficiency is a rare inborn disease characterized with glucose metabolism defects, which leads to neurological dysfunction, serum lactic acid buildup and a resultant trend of metabolic acidosis. Although the ketogenic diet (KD) is the first-line treatment for PDC deficiency, there is currently no widely accepted consensus on specific implementation of KD for this condition. Due to the combined effect of pre-existing hyperlactacidemia and KD-induced ketoacidosis that can further exacerbate metabolic disturbances, maintaining metabolic homeostasis should be prioritized during the implementation of KD.CASE PRESENTATION: Herein, the authors present a 6-year-old boy with lactic acidosis, ataxia, hypotonia and neuromotor development retardation. The KD was started after the patient was diagnosed with PDC deficiency based on genetic testing. The initiation with classic KD resulted in severe non-diabetic ketoacidosis with elevated anion gap, which was promptly alleviated by dextrose supplementation and dietary modification to a less-restrictive KD. Long-term supervision demonstrated the efficacy of a modified KD in improving both clinical course and metabolic acidosis of the patient.
CONCLUSIONS: This rare case adds to the limited evidence of KD application in PDC deficiency, and provides valuable insights into the importance of reasonably lowering the ketogenic ratio of KD at the start of treatment to reduce the risk of metabolic acidosis.

Keywords: Acidosis; Ketogenic diet; Lactic acid; Non-diabetic ketoacidosis; Pyruvate dehydrogenase complex deficiency

DOI: https://doi.org/10.1186/s12887-024-05054-w

bioRxiv. 2024 Sep 21. pii: 2024.09.17.613577. [Epub ahead of print]

Integration of metabolomic and transcriptomic analyses reveals novel regulatory functions of the ChREBP transcription factor in energy metabolism.

Jie An, Inna Astapova, Guofang Zhang, Andrew L Cangelosi, Olga Ilkayeva, Hannah Marchuk, Michael J Muehlbauer, Tabitha George, Joseph Brozinick, Mark A Herman, Christopher B Newgard.

Carbohydrate Response Element-Binding Protein (ChREBP) is a transcription factor that activates key genes involved in glucose, fructose, and lipid metabolism in response to carbohydrate feeding, but its other potential roles in metabolic homeostasis have not been as well studied. We used liver-selective GalNAc-siRNA technology to suppress expression of ChREBP in rats fed a high fat/high sucrose diet and characterized hepatic and systemic responses by integrating transcriptomic and metabolomic analyses. GalNAc-siChREBP-treated rats had lower levels of multiple short-chain acyl CoA metabolites compared to rats treated with GalNAc-siCtrl containing a non-targeting siRNA sequence. These changes were related to a sharp decrease in free CoA levels in GalNAc-siChREBP treated-rats, accompanied by lower expression of transcripts encoding enzymes and transporters involved in CoA biosynthesis. These activities of ChREBP likely contribute to its complex effects on hepatic lipid and energy metabolism. While core enzymes of fatty acid (FA) oxidation are induced by ChREBP knockdown, accumulation of liver acylcarnitines and circulating ketones indicate diversion of acetyl CoA to ketone production rather than complete oxidation in the TCA cycle. Despite strong suppression of pyruvate kinase and activation of pyruvate dehydrogenase, pyruvate levels were maintained, likely via increased expression of pyruvate transporters, and decreased expression of lactate dehydrogenase and alanine transaminase. GalNAc-siChREBP treatment increased hepatic citrate and isocitrate levels while decreasing levels of distal TCA cycle intermediates. The drop in free CoA levels, needed for the 2-ketoglutarate dehydrogenase reaction, as well as a decrease in transcripts encoding the anaplerotic enzymes pyruvate carboxylase, glutamate dehydrogenase, and aspartate transaminase likely contributed to these effects. GalNAc-siChREBP treatment caused striking increases in PRPP and ZMP/AICAR levels, and decreases in GMP, IMP, AMP, NaNM, NAD(P), and NAD(P)H levels, accompanied by reduced expression of enzymes that catalyze late steps in purine and NAD synthesis. ChREBP suppression also increased expression of a set of plasma membrane amino acid transporters, possibly as an attempt to replenish TCA cycle intermediates. In sum, combining transcriptomic and metabolomic analyses has revealed regulatory functions of ChREBP that go well beyond its canonical roles in control of carbohydrate and lipid metabolism to now include mitochondrial metabolism and cellular energy balance.

DOI: https://doi.org/10.1101/2024.09.17.613577