Mitophagy and Oxidative Stress in Cancer and Aging: Focus on Sirtuins and Nanomaterials

Abstract

Mitochondria are the cellular center of energy production and of several important metabolic processes. Mitochondrion health is maintained with a substantial intervention of mitophagy, a process of macroautophagy that degrades selectively dysfunctional and irreversibly damaged organelles. Because of its crucial duty, alteration in mitophagy can cause functional and structural adjustment in the mitochondria, changes in energy production, loss of cellular adaptation, and cell death. In this review, we discuss the dual role that mitophagy plays in cancer and age-related pathologies, as a consequence of oxidative stress, evidencing the triggering stimuli and mechanisms and suggesting the molecular targets for its therapeutic control. Finally, a section has been dedicated to the interplay between mitophagy and therapies using nanoparticles that are the new frontier for a direct and less invasive strategy.

Figure 1

Autophagosomes accumulate into myocardiocytes due to the presence of chloroquine which blocks the fusion between primary lysosomes and autophagosomes. (a) Large autophagosomes (A) with different cytoplasmic components, mainly degraded lipid membranes, and glycogen. (b) Magnification of the detail indicated in the square. m: mitochondria.

Figure 2

Mitochondria (m) have been damaged by different physiopathological conditions. (a) Mutated, misfolded, and fibrillary polymerized mitochondrial proteins may accumulate into the matrix giving rise to giant mitochondria with paracrystalline inclusions. They appear surrounded by endoplasmic reticulum (ER) membranes, indicating a process of segregation for autophagocytosis. (b) Antibiotics affecting bacterial protein synthesis may interfere with mitochondrial protein synthesis producing enlarged mitochondria (m) with paracrystalline inclusions and bizarre shape. Also, in this case, the close interaction with endoplasmic reticulum membranes suggests a process of segregation for mitophagy (N: nucleus). (c) Swollen liver mitochondria (m) after 3 hours of ischemia: they show a number of pathological changes: volume increase, dishomogeneous electron-clear and sometimes vacuolized matrix, fragmented cristae, and sometimes interrupted outer membrane. Indeed, they appear, together with apparently intact peroxisomes (p), surrounded by endoplasmic reticulum (ER) which indicates the autophagocytic process. (d) Mitochondria (m) from the glomerular zone of a suprarenal cortex which has been intensively stimulated by ACTH. The consequent hypertrophy includes also an increase of mitochondrial growth (number and volume) and an accelerated turnover as suggested by the increased mitophagy (A).

Figure 3

Sequence and molecular details of the selective mitophagy. When mitochondria undergo decrease in membrane potential (or different stress stimuli), PINK1, localized on the mitochondrial membrane, recruits Parkin that polyubiquitinates MOM protein and induces the autophagosome formation. Then, lysosome fuses with the autophagosome (autophagolysosome) and the degraded material can be recycled or disposed.

Figure 4

Electron micrograph of a mitophagic vacuole (A) containing a well-preserved mitochondrion (m). Molecules involved in selective mitophagy are indicated.

Figure 5

Schematic representation of all the aspects related to mitophagy. Two basic mechanisms have been elucidated involving a different set of molecules in relation to the prototype damage: the mitochondrial depolarization and hypoxia, starvation, and genes controlled by some master transcription factors (p53, RB/E2F, FoxOS, NFkB, sirtuins, and others).