Mitochondria-Ros Crosstalk in the Control of Cell Death and Aging

Reactive oxygen species (ROS) are highly reactive molecules, mainly generated inside mitochondria that can oxidize DNA, proteins, and lipids. At physiological levels, ROS function as “redox messengers” in intracellular signalling and regulation, whereas excess ROS induce cell death by promoting the intrinsic apoptotic pathway. Recent work has pointed to a further role of ROS in activation of autophagy and their importance in the regulation of aging. This review will focus on mitochondria as producers and targets of ROS and will summarize different proteins that modulate the redox state of the cell. Moreover, the involvement of ROS and mitochondria in different molecular pathways controlling lifespan will be reported, pointing out the role of ROS as a “balance of power,” directing the cell towards life or death

p66Shc Aging Protein in Control of Fibroblasts Cell Fate

Reactive oxygen species (ROS) are wieldy accepted as one of the main factors of the aging process. These highly reactive compounds modify nucleic acids, proteins and lipids and affect the functionality of mitochondria in the first case and ultimately of the cell. Any agent or genetic modification that affects ROS production and detoxification can be expected to influence longevity. On the other hand, genetic manipulations leading to increased longevity can be expected to involve cellular changes that affect ROS metabolism. The 66-kDa isoform of the growth factor adaptor Shc (p66Shc) has been recognized as a relevant factor to the oxygen radical theory of aging. The most recent data indicate that p66Shc protein regulates life span in mammals and its phosphorylation on serine 36 is important for the initiation of cell death upon oxidative stress. Moreover, there is strong evidence that apart from aging, p66Shc may be implicated in many oxidative stress-associated pathologies, such as diabetes, mitochondrial and neurodegenerative disorders and tumorigenesis. This article summarizes recent knowledge about the role of p66Shc in aging and senescence and how this protein can influence ROS production and detoxification, focusing on studies performed on skin and skin fibroblasts

Mitochondria-Associated Membranes: Composition, Molecular Mechanisms, and Physiopathological Implications

Significance: In all cells, the endoplasmic reticulum (ER) and mitochondria are physically connected to form junctions termed mitochondria-associated membranes ( MAMs). This subcellular compartment is under intense investigation because it represents a ‘‘hot spot’’ for the intracellular signaling of important pathways, including the synthesis of cholesterol and phospholipids, calcium homeostasis, and reactive oxygen species (ROS) generation and activity. Recent Advances: The advanced methods currently used to study this fascinating intracellular microdomain in detail have enabled the identification of the molecular composition of MAMs and their involvement within different physiopathological contexts. Critical Issues: Here, we review the knowledge regarding (i) MAMs composition in terms of protein composition, (ii) the relationship between MAMs and ROS, (iii) the involvement of MAMs in cell death programs with particular emphasis within the tumor context, (iv) the emerging role of MAMs during inflammation, and (v) the key role of MAMs alterations in selected neurological disorders. Future Directions: Whether alterations in MAMs represent a response to the disease pathogenesis or directly contribute to the disease has not yet been unequivocally established. In any case, the signaling at the MAMs represents a promising pharmacological target for several important human diseases

Relation Between Mitochondrial Membrane Potential and ROS Formation

Mitochondria are considered the main source of reactive oxygen species (ROS) in the cell. For this reason they have been recognized as a source of various pathological conditions as well as aging. Chronic increase in the rate of ROS production is responsible for the accumulation of ROS-associated damages in DNA, proteins, and lipids and may result in progressive cell dysfunctions and, in a consequence, apoptosis, increasing the overall probability of an organism's pathological conditions. The superoxide anion is the main undesired by-product of mitochondrial oxidative phosphorylation. Its production is triggered by a leak of electrons from the mitochondrial respiratory chain and the reaction of these electrons with O-2. Superoxide dismutase (MnSOD, SOD2) from the mitochondrial matrix, as well as superoxide dismutase (Cu/ ZnSOD, SOD1) present in small amounts in the mitochondrial intramembrane space, converts superoxide anion to hydrogen peroxide, which can be then converted by catalase to harmless H2O.In the chapter we describe a relation between mitochondrial membrane potential and the rate of ROS formation. We present different methods applicable for isolated mitochondria or intact cells. We also present experiments demonstrating that a magnitude and a direction (increase or decrease) of a change in mitochondrial ROS production depend on the metabolic state of this organelle

Recovering Mitochondrial Function in Patients’ Fibroblasts

Despite the fact that majority of studies done using different compounds with antioxidant properties showing pivotal effect on oxidative phosphorylation or glycolytic ATP production, it is still difficult to discuss efficient therapeutic solutions for patients affected by mitochondrial diseases or mitochondrial dysfunction-associated disorders. Since most of the mitochondrial disorders are manifested in tissues or organs that demand high-energy, many experimental studies have described that the pivotal effect of the tested compounds comes from the use of the skin fibroblasts from patients. In this chapter, we have gathered information about these studies and describe the effect of such treatment on mitochondrial function and the attenuation of oxidative stress in patients’ fibroblasts

Mitochondria-associated membranes (MAMs) as hotspot Ca 2+ signaling units

none13noneBononi, Angela; Missiroli, Sonia; Poletti, Federica; Suski, Jan M.; Agnoletto, Chiara; Bonora, Massimo; De Marchi, Elena; Giorgi, Carlotta; Marchi, Saverio; Patergnani, Simone; Rimessi, Alessandro; Wieckowski, Mariusz R.; Pinton, Paolo*Bononi, Angela; Missiroli, Sonia; Poletti, Federica; Suski, Jan M.; Agnoletto, Chiara; Bonora, Massimo; De Marchi, Elena; Giorgi, Carlotta; Marchi, Saverio; Patergnani, Simone; Rimessi, Alessandro; Wieckowski, Mariusz R.; Pinton, Paol

Mitochondria-Associated Membranes (MAMs) as Hotspot Ca(2+) Signaling Units.

The tight interplay between endoplasmic reticulum (ER) and mitochondria is a key determinant of cell function and survival through the control of intracellular calcium (Ca(2+)) signaling. The specific sites of physical association between ER and mitochondria are known as mitochondria-associated membranes (MAMs). It has recently become clear that MAMs are crucial for highly efficient transmission of Ca(2+) from the ER to mitochondria, thus controlling fundamental processes involved in energy production and also determining cell fate by triggering or preventing apoptosis. In this contribution, we summarize the main features of the Ca(2+)-signaling toolkit, covering also the latest breakthroughs in the field, such as the identification of novel candidate proteins implicated in mitochondrial Ca(2+) transport and the recent direct characterization of the high-Ca(2+) microdomains between ER and mitochondria. We review the main functions of these two organelles, with special emphasis on Ca(2+) handling and on the structural and molecular foundations of the signaling contacts between them. Additionally, we provide important examples of the physiopathological role of this cross-talk, briefly describing the key role played by MAMs proteins in many diseases, and shedding light on the essential role of mitochondria-ER interactions in the maintenance of cellular homeostasis and the determination of cell fate