Mitochondrial pathways in human health and aging

Bornstein, Rebecca; González, Brenda; Johnson, Simon C.

doi:10.1016/j.mito.2020.07.007

Cited by 55 publications

(33 citation statements)

References 174 publications

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“…Previous in vitro experiments demonstrated that, in fibroblasts, redox balance and extracellular matrix homeostasis were affected by aging and that, similarly to PXE fibroblasts (Boraldi et al, 2013), aged cells were more susceptible to pro-osteogenic signals (Boraldi et al, 2010(Boraldi et al, , 2015. Since the aging process has been associated to disrupted mitochondrial function (Miquel and Fleming, 1984;Bornstein et al, 2020), it can be suggested that mitochondria can also contribute to the pathologic phenotype of PXE fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

Lofaro

Boraldi

García-Fernández

et al. 2020

Front. Cell Dev. Biol.

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Pseudoxanthoma elasticum (PXE) is a genetic disease considered as a paradigm of ectopic mineralization disorders, being characterized by multisystem clinical manifestations due to progressive calcification of skin, eyes, and the cardiovascular system, resembling an age-related phenotype. Although fibroblasts do not express the pathogenic ABCC6 gene, nevertheless these cells are still under investigation because they regulate connective tissue homeostasis, generating the “arena” where cells and extracellular matrix components can promote pathologic calcification and where activation of pro-osteogenic factors can be associated to pathways involving mitochondrial metabolism. The aim of the present study was to integrate structural and bioenergenetic features to deeply investigate mitochondria from control and from PXE fibroblasts cultured in standard conditions and to explore the role of mitochondria in the development of the PXE fibroblasts’ pathologic phenotype. Proteomic, biochemical, and morphological data provide new evidence that in basal culture conditions (1) the protein profile of PXE mitochondria reveals a number of differentially expressed proteins, suggesting changes in redox balance, oxidative phosphorylation, and calcium homeostasis in addition to modified structure and organization, (2) measure of oxygen consumption indicates that the PXE mitochondria have a low ability to cope with a sudden increased need for ATP via oxidative phosphorylation, (3) mitochondrial membranes are highly polarized in PXE fibroblasts, and this condition contributes to increased reactive oxygen species levels, (4) ultrastructural alterations in PXE mitochondria are associated with functional changes, and (5) PXE fibroblasts exhibit a more abundant, branched, and interconnected mitochondrial network compared to control cells, indicating that fusion prevail over fission events. In summary, the present study demonstrates that mitochondria are modified in PXE fibroblasts. Since mitochondria are key players in the development of the aging process, fibroblasts cultured from aged individuals or aged in vitro are more prone to calcify, and in PXE, calcified tissues remind features of premature aging syndromes; it can be hypothesized that mitochondria represent a common link contributing to the development of ectopic calcification in aging and in diseases. Therefore, ameliorating mitochondrial functions and cell metabolism could open new strategies to positively regulate a number of signaling pathways associated to pathologic calcification.

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Section: Introductionmentioning

confidence: 99%

Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

Lofaro

Boraldi

García-Fernández

et al. 2020

Front. Cell Dev. Biol.

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“…Therefore, diseases where the progression can be correlated with or compensated for mitochondrial function are collectively referred as mitochondrial diseases. At present, in addition to neurodegenerative disorders ( Baldassarro et al, 2019 ), there are numerous diseases related to abnormal mitochondrial structure and function, including mental diseases ( Ashwini et al, 2015 ), tumor ( Schubert et al, 2020 ), aging ( Bornstein et al, 2020 ), cardiovascular disease ( Veloso et al, 2019 ), diabetes ( Szendroedi et al, 2012 ), etc. Therapeutics which target mitochondria also result in positive responses in some cases ( Jeena et al, 2019 ).…”

Section: The Structure Function and Related Diseases Of Mitochondriamentioning

confidence: 99%

Recent Advances in Chemical Biology of Mitochondria Targeting

et al. 2021

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Mitochondria are vital subcellular organelles that generate most cellular chemical energy, regulate cell metabolism and maintain cell function. Mitochondrial dysfunction is directly linked to numerous diseases including neurodegenerative disorders, diabetes, thyroid squamous disease, cancer and septicemia. Thus, the design of specific mitochondria-targeting molecules and the realization of real-time acquisition of mitochondrial activity are powerful tools in the study and treatment of mitochondria dysfunction in related diseases. Recent advances in mitochondria-targeting agents have led to several important mitochondria chemical probes that offer the opportunity for selective targeting molecules, novel biological applications and therapeutic strategies. This review details the structural and physiological functional characteristics of mitochondria, and comprehensively summarizes and classifies mitochondria-targeting agents. In addition, their pros and cons and their related chemical biological applications are discussed. Finally, the potential biomedical applications of these agents are briefly prospected.

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“…Mitochondrial dysfunction is a hallmark of the aging process ( López-Otín et al, 2013 ; Bornstein et al, 2020 ). Consistently, genetic mutations that dysregulate mitochondrial function clearly associate with accelerated aging phenotypes and increased susceptibility to disease ( Bornstein et al, 2020 ). However, mitochondrial function does not necessarily show a linear decline during the course of aging.…”

Section: Targeting Mitochondria To Delay Agingmentioning

confidence: 99%

“…Accumulating defects on the cellular level can result in cellular dysfunction that impairs normal physiology. This damage can be of extrinsic origin e.g., mutagenic radiation and toxins, or intracellular origin, like harmful reactive oxygen species (ROS) generated by defective mitochondrial respiration ( Bornstein et al, 2020 ), advanced glycation end products ( Semba et al, 2010 ) or the accumulation of toxic protein aggregates ( Hipp et al, 2019 ). The consequences of such harm are particularly devastating to post-mitotic, fully differentiated cells with low cellular turnover rates, such as neuronal cells and cardiomyocytes ( Ernst et al, 2014 ; Eschenhagen et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Targeting the Mitochondria-Proteostasis Axis to Delay Aging

Zimmermann

Madreiter‐Sokolowski

Stryeck

et al. 2021

Front. Cell Dev. Biol.

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Human life expectancy continues to grow globally, and so does the prevalence of age-related chronic diseases, causing a huge medical and economic burden on society. Effective therapeutic options for these disorders are scarce, and even if available, are typically limited to a single comorbidity in a multifaceted dysfunction that inevitably affects all organ systems. Thus, novel therapies that target fundamental processes of aging itself are desperately needed. In this article, we summarize current strategies that successfully delay aging and related diseases by targeting mitochondria and protein homeostasis. In particular, we focus on autophagy, as a fundamental proteostatic process that is intimately linked to mitochondrial quality control. We present genetic and pharmacological interventions that effectively extend health- and life-span by acting on specific mitochondrial and pro-autophagic molecular targets. In the end, we delve into the crosstalk between autophagy and mitochondria, in what we refer to as the mitochondria-proteostasis axis, and explore the prospect of targeting this crosstalk to harness maximal therapeutic potential of anti-aging interventions.

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Mitochondrial pathways in human health and aging

Cited by 55 publications

References 174 publications

Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

Recent Advances in Chemical Biology of Mitochondria Targeting

Targeting the Mitochondria-Proteostasis Axis to Delay Aging

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