bims-misrem 2020-07-26 papers

Issue of 2020‒07‒26
four papers selected by
Rafael Antonio Casuso Pérez
University of Granada

Biochim Biophys Acta Mol Basis Dis. 2020 Jul 19. pii: S0925-4439(20)30247-7. [Epub ahead of print] 165899

Endoplasmic reticulum stress-mediated mitochondrial dysfunction in aged hearts.

Qun Chen, Arun Samidurai, Jeremy Thompson, Ying Hu, Anindita Das, Belinda Willard, Edward J Lesnefsky.

Aging impairs the mitochondrial electron transport chain (ETC), especially in interfibrillar mitochondria (IFM). Mitochondria are in close contact with the endoplasmic reticulum (ER). Induction of ER stress leads to ETC injury in adult heart mitochondria. We asked if ER stress contributes to the mitochondrial dysfunction during aging. Subsarcolemmal mitochondria (SSM) and IFM were isolated from 3, 18, and 24 mo. C57Bl/6 mouse hearts. ER stress progressively increased with age, especially in 24 mo. mice that manifest mitochondrial dysfunction. OXPHOS was decreased in 24 mo. IFM oxidizing complex I and complex IV substrates. Proteomic analysis showed that the content of multiple complex I subunits was decreased in IFM from 24 mo. hearts, but remained unchanged in in 18 mo. IFM without a decrease in OXPHOS. Feeding 24 mo. old mice with 4-phenylbutyrate (4-PBA) for two weeks attenuated the ER stress and improved mitochondrial function. These results indicate that ER stress contributes to the mitochondrial dysfunction in aged hearts. Attenuation of ER stress is a potential approach to improve mitochondrial function in aged hearts.

Keywords: 4-Phenylbutyrate; Aging; Complex I; Electron transport chain

DOI: https://doi.org/10.1016/j.bbadis.2020.165899

J Appl Physiol (1985). 2020 Jul 23.

Improvements in skeletal muscle fiber size with resistance training are age-dependent in older adults: a systematic review and meta-analysis.

Chad R Straight, Michael V Fedewa, Michael J Toth, Mark S Miller.

As studies examining the hypertrophic effects of resistance training (RT) at the cellular level have produced inconsistent results, we performed a systematic review and meta-analysis to investigate muscle fiber size before and after a structured RT intervention in older adults. A random-effects model was used to calculate mean effect size (ES) and 95% confidence intervals (CI). Thirty-five studies were included (age range: 59.0-88.5 years), and 44 and 30 effects were used to estimate RT impact on myosin heavy chain (MHC) I and II fiber size. RT produced moderate-to-large increases in MHC I (ES=+0.51, 95%CI +0.31 to +0.71; p<0.001) and II (ES=+0.81, 95%CI +0.56 to +1.05; p<0.001) fiber size, with men and women having a similar response. Age was negatively associated with change in muscle fiber size for both fiber types (MHC I: R2=0.11, β=-0.33, p=0.002; MHC II: R2=0.10, β=-0.32, p=0.04), indicating a less robust hypertrophic response as age increases in older adults. Unexpectedly, a higher training intensity (defined as percentage of one-repetition maximum) was associated with a smaller increase in MHC II fiber size (R2=15.09%, β=-0.39, p=0.01). Notably, MHC II fiber subtypes (IIA, IIX, IIAX) were examined less frequently, but RT improved their size. Overall, our findings indicate that RT induces cellular hypertrophy in older adults, although the effect is attenuated with increasing age. In addition, hypertrophy of MHC II fibers was reduced with higher training intensity, which may suggest a failure of muscle fibers to hypertrophy in response to high loads in older adults.

Keywords: aging; cellular; exercise; hypertrophy; myosin

DOI: https://doi.org/10.1152/japplphysiol.00170.2020

Acta Pharmacol Sin. 2020 Jul 21.

Mitochondrial Ca2+ regulation in the etiology of heart failure: physiological and pathophysiological implications.

Hai-Xia Xu, Su-Mei Cui, Ying-Mei Zhang, Jun Ren.

Heart failure (HF) represents one of the leading causes of cardiovascular diseases with high rates of hospitalization, morbidity and mortality worldwide. Ample evidence has consolidated a crucial role for mitochondrial injury in the progression of HF. It is well established that mitochondrial Ca2+ participates in the regulation of a wide variety of biological processes, including oxidative phosphorylation, ATP synthesis, reactive oxygen species (ROS) generation, mitochondrial dynamics and mitophagy. Nonetheless, mitochondrial Ca2+ overload stimulates mitochondrial permeability transition pore (mPTP) opening and mitochondrial swelling, resulting in mitochondrial injury, apoptosis, cardiac remodeling, and ultimately development of HF. Moreover, mitochondria possess a series of Ca2+ transport influx and efflux channels, to buffer Ca2+ in the cytoplasm. Interaction at mitochondria-associated endoplasmic reticulum membranes (MAMs) may also participate in the regulation of mitochondrial Ca2+ homeostasis and plays an essential role in the progression of HF. Here, we provide an overview of regulation of mitochondrial Ca2+ homeostasis in maintenance of cardiac function, in an effort to identify novel therapeutic strategies for the management of HF.

Keywords: ATP synthesis, ROS production; MAMs; heart failure; mitochondrial Ca2+ homeostasis; mitochondrial Ca2+ transport; myocardial apoptosis

DOI: https://doi.org/10.1038/s41401-020-0476-5

Proc Natl Acad Sci U S A. 2020 Jul 23. pii: 202003236. [Epub ahead of print]

Mitochondria-lysosome contacts regulate mitochondrial Ca2+ dynamics via lysosomal TRPML1.

Wesley Peng, Yvette C Wong, Dimitri Krainc.

Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle contacts between mitochondria and lysosomes were identified and found to regulate mitochondrial dynamics. However, whether mitochondria-lysosome contacts serve additional functions by facilitating the direct transfer of metabolites or ions between the two organelles has not been elucidated. Here, using high spatial and temporal resolution live-cell microscopy, we identified a role for mitochondria-lysosome contacts in regulating mitochondrial calcium dynamics through the lysosomal calcium efflux channel, transient receptor potential mucolipin 1 (TRPML1). Lysosomal calcium release by TRPML1 promotes calcium transfer to mitochondria, which was mediated by tethering of mitochondria-lysosome contact sites. Moreover, mitochondrial calcium uptake at mitochondria-lysosome contact sites was modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Since loss of TRPML1 function results in the lysosomal storage disorder mucolipidosis type IV (MLIV), we examined MLIV patient fibroblasts and found both altered mitochondria-lysosome contact dynamics and defective contact-dependent mitochondrial calcium uptake. Thus, our work highlights mitochondria-lysosome contacts as key contributors to interorganelle calcium dynamics and their potential role in the pathophysiology of disorders characterized by dysfunctional mitochondria or lysosomes.

Keywords: TRPML1; calcium; lysosomal storage disorder; mitochondria–lysosome contacts; interorganelle membrane contact sites

DOI: https://doi.org/10.1073/pnas.2003236117