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1. Analysis of Mitochondrial Function, Structure, and Intracellular Organization In Situ in Cardiomyocytes and Skeletal Muscles

   https://doi.org/10.3390/ijms23042252  

   Kuznetsov, Andrey V.; Javadov, Sabzali; Margreiter, Raimund; Hagenbuchner, Judith; Ausserlechner, Michael J. (February 2022, International Journal of Molecular Sciences)

   Analysis of the function, structure, and intracellular organization of mitochondria is important for elucidating energy metabolism and intracellular energy transfer. In addition, basic and clinically oriented studies that investigate organ/tissue/cell dysfunction in various human diseases, including myopathies, cardiac/brain ischemia-reperfusion injuries, neurodegenerative diseases, cancer, and aging, require precise estimation of mitochondrial function. It should be noted that the main metabolic and functional characteristics of mitochondria obtained in situ (in permeabilized cells and tissue samples) and in vitro (in isolated organelles) are quite different, thereby compromising interpretations of experimental and clinical data. These differences are explained by the existence of the mitochondrial network, which possesses multiple interactions between the cytoplasm and other subcellular organelles. Metabolic and functional crosstalk between mitochondria and extra-mitochondrial cellular environments plays a crucial role in the regulation of mitochondrial metabolism and physiology. Therefore, it is important to analyze mitochondria in vivo or in situ without their isolation from the natural cellular environment. This review summarizes previous studies and discusses existing approaches and methods for the analysis of mitochondrial function, structure, and intracellular organization in situ. 

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2. Beta-Amyloid Instigates Dysfunction of Mitochondria in Cardiac Cells

   https://doi.org/10.3390/cells11030373  

   Jang, Sehwan; Chapa-Dubocq, Xavier R.; Parodi-Rullán, Rebecca M.; Fossati, Silvia; Javadov, Sabzali (February 2022, Cells)

   Alzheimer’s disease (AD) includes the formation of extracellular deposits comprising aggregated β-amyloid (Aβ) fibers associated with oxidative stress, inflammation, mitochondrial abnormalities, and neuronal loss. There is an associative link between AD and cardiac diseases; however, the mechanisms underlying the potential role of AD, particularly Aβ in cardiac cells, remain unknown. Here, we investigated the role of mitochondria in mediating the effects of Aβ1-40 and Aβ1-42 in cultured cardiomyocytes and primary coronary endothelial cells. Our results demonstrated that Aβ1-40 and Aβ1-42 are differently accumulated in cardiomyocytes and coronary endothelial cells. Aβ1-42 had more adverse effects than Aβ1-40 on cell viability and mitochondrial function in both types of cells. Mitochondrial and cellular ROS were significantly increased, whereas mitochondrial membrane potential and calcium retention capacity decreased in both types of cells in response to Aβ1-42. Mitochondrial dysfunction induced by Aβ was associated with apoptosis of the cells. The effects of Aβ1-42 on mitochondria and cell death were more evident in coronary endothelial cells. In addition, Aβ1-40 and Aβ1-42 significantly increased Ca2+ -induced swelling in mitochondria isolated from the intact rat hearts. In conclusion, this study demonstrates the toxic effects of Aβ on cell survival and mitochondria function in cardiac cells. 

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3. Metabolic Pathways Linking Atherosclerotic Cardiovascular Disease With Metabolic Dysfunction-Associated Steatotic Liver Disease

   https://doi.org/10.1007/s11883-026-01425-z  

   Richard, Koral_S E; Rohilla, Sumati; Gade, Reethika; Arias, Fabio; Rom, Oren (December 2026, Current Atherosclerosis Reports)

   Abstract Purpose of ReviewThis review explores the metabolic pathways dysregulated in both atherosclerotic cardiovascular disease (ASCVD) and metabolic dysfunction-associated steatotic liver disease (MASLD), focusing on lipid, carbohydrate, amino acid, and energy metabolism and the specific alterations within major contributing cell types. Recent FindingsIn the setting of metabolic syndrome, lipid and carbohydrate overload impair hepatic metabolism, resulting in the accumulation of lipotoxic species and ensuing cellular damage, inflammation, oxidative stress, and cardiovascular consequences. Amino acid metabolism is emerging as a key regulator of cell fate and function in both MASLD and ASCVD. Mitochondrial dysfunction and cellular stress promote a pseudo-Warburg effect, shifting cells from efficient oxidative phosphorylation to anaerobic glycolysis and impairing homeostasis. Emerging therapies targeting hepatic metabolism to reduce cardiovascular risk and MASLD burden hold promise for future dual treatments. SummaryMASLD and ASCVD arise from common metabolic derangements that converge on shared cellular and molecular pathways. Defining these cross-tissue mechanisms may enable the development of integrated therapeutic approaches aimed at jointly mitigating hepatic and vascular injury, thus redefining treatment paradigms in cardiometabolic disease. 

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4. UV irradiation alters TFAM binding specificity and compaction of DNA

   https://doi.org/10.7554/eLife.108862  

   King, DE; Beard, EE; Satusky, MJ; George, A; Ryde, I; Johnson, C; Dolan, EL; Zhang, Y; Zhu, W; Wilkins, H; et al (March 2026, eLife)

   Mitochondria lack nucleotide excision repair; however, mitochondrial DNA (mtDNA) is resistant to mutation accumulation following DNA damage. These observations suggest additional damage sensing or protection mechanisms. Transcription Factor A, Mitochondrial (TFAM) compacts mtDNA into nucleoids and binds differentially to certain forms of DNA damage. As such, TFAM has emerged as a candidate for protecting mtDNA or sensing damage. To examine the possibilities that TFAM might protect DNA from damage or act as a damage sensing protein for irreparable forms of mtDNA damage, we used live-cell imaging and HeLa cell-based assays, atomic force microscopy (AFM), and high-throughput protein-DNA binding assays to characterize the binding properties of human TFAM to ultraviolet-C (UVC) irradiated DNA and the cellular consequences of UVC irradiation. Our cell data show increased TFAM mRNA after exposure and suggest an increase in mtDNA degradation without a loss in mitochondrial membrane potential that might trigger mitophagy. Our protein-DNA binding assays indicate a reduction in sequence specificity of TFAM following UVC irradiation and a redistribution of TFAM binding throughout the mitochondrial genome. Our AFM data show increased compaction of DNA by TFAM in the presence of damage. Despite the TFAM-mediated compaction of mtDNA in vitro, we do not observe any protective effect of increased TFAM protein on DNA damage formation in cells or in vitro. Increased TFAM protein did not alter levels of mtDNA damage over time after UVC exposure in vivo, but knockdown of TFAM did alter mtDNA damage levels in HeLa cells both at baseline and after UVC exposure. Taken together, these studies indicate that UVC-induced DNA damage alters TFAM binding and promotes compaction by TFAM in vitro. We hypothesize that TFAM may act as a damage sensing protein in vivo, sequestering damaged genomes to prevent mutagenesis by facilitating removal or suppression of replication. 

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5. Lineage‐Mismatched Mitochondrial Replacement in an Inducible Mitochondrial Depletion Model Effectively Restores the Original Proteomic Landscape of Recipient Cells

   https://doi.org/10.1002/adbi.202200246  

   Capelluto, Fausto; Alberico, Hannah; Ledo‐Hopgood, Paula; Tilly, Jonathan L.; Woods, Dori C. (April 2023, Advanced Biology)

   In addition to critical roles in bioenergetics, mitochondria are key contributors to the regulation of many other functions in cells, ranging from steroidogenesis to apoptosis. Numerous studies further demonstrate that cell type-specific differences exist in mitochondria, with cells of a given lineage tailoring their endogenous mitochondrial population to suit specific functional needs. These findings, coupled with studies of the therapeutic potential of mitochondrial transplantation, provide a strong impetus to better understand how mitochondria can influence cell function or fate. Here an inducible mitochondrial depletion modelis used to study how cells lacking endogenous mitochondria respond, on a global protein expression level, to transplantation with lineage-mismatched (LM) mitochondria. It is shown that LM mitochondrial transplantation does not alter the proteomic profile in nonmitochondria-depleted recipient cells; however, enforced depletion of endogenous mitochondria results in dramatic changes in the proteomic landscape, which returns to the predepletion state following internalization of LM mitochondria. These data, derived from a cell system that can be rendered free of influence by endogenous mitochondria, indicate that transplantation of mitochondria-even from a source that differs significantly from the recipient cell population, effectively restores a normal proteomic landscape to cells lacking their own mitochondria. 

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