The coordination of nuclear and mitochondrial communication during aging and calorie restriction

Abstract

Mitochondria are dynamic organelles that integrate environmental signals to regulate energy production, apoptosis and Ca(2+) homeostasis. Not surprisingly, mitochondrial dysfunction is associated with aging and the pathologies observed in age-related diseases. The vast majority of mitochondrial proteins are encoded in the nuclear genome, and so communication between the nucleus and mitochondria is essential for maintenance of appropriate mitochondrial function. Several proteins have emerged as major regulators of mitochondrial gene expression, capable of increasing transcription of mitochondrial genes in response to the physiological demands of the cell. In this review, we will focus on PGC-1alpha, SIRT1, AMPK and mTOR and discuss how these proteins regulate mitochondrial function and their potential involvement in aging, calorie restriction and age-related disease. We will also discuss the pathways through which mitochondria signal to the nucleus. Although such retrograde signaling is not well studied in mammals, there is growing evidence to suggest that it may be an important area for future aging research. Greater understanding of the mechanisms by which mitochondria and the nucleus communicate will facilitate efforts to slow or reverse the mitochondrial dysfunction that occurs during aging.

Figure 1

Mammalian mitochondrial retrograde signaling pathways. Mitochondrial activity can influence cellular NAD⁺/NADH ratios, cytosolic free Ca²⁺ concentrations, ATP/ADP ratios and cellular oxidative stress. Electrons from cytosolic NADH can be transferred to mitochondrial NAD⁺ to form NADH via the malate-aspartate shuttle (1,2). This NADH, along with the NADH generated by the TCA cycle, donates electrons to complex I of the mitochondrial electron transport chain, regenerating NAD⁺. Electrons are passed between the complexes of OXPHOS (I, II, III, IV) and their energy is used to pump protons into the intermembrane space. Complex V uses this proton gradient to synthesize ATP, which is then exchanged for cytosolic ADP by ANT (5). Small molecules, such as ADP, ATP and Ca²⁺ diffuse cross the outer mitochondrial membrane through VDAC. Mitochondrial membrane potential drives Ca²⁺ entry into the matrix through a Ca²⁺ uniporter (3), and Ca²⁺ is transferred out through an antiporter that exchanges Na⁺/H⁺ for Ca²⁺(4). Ca²⁺ can stimulate activity of three enzymes in the TCA cycle, resulting in increased electron transport. Electrons can leak out of the electron transport chain at complex I and complex III, combining with O₂ to form superoxide, which can be converted by SOD2 to H₂O₂ or combine with NO to form ONOO⁻. Superoxide, ONOO⁻ and H₂O₂ can all cause oxidative damage, and H₂O₂ can diffuse out of the mitochondria to cause oxidative stress and trigger redox signaling. Ca²⁺ is required for synthesis of NO, and NO can inhibit complex IV, increasing electron leakage. Each of these outputs (shown in green) can act as signaling molecules and influence the activity of various signaling pathways with the potential to regulate transcription of mitochondrial genes. Increases in the NAD/NADH ratio are thought to activate SIRT1, which can deacetylate and activate PGC-1α. Increased cytosolic Ca²⁺ triggers a signaling cascade that increases phosphorylation of CREB, stimulating its ability to activate transcription of the PGC-1α gene. A rise in the ADP/ATP ratio activates AMPK, which can inhibit mTORC1 activity by phosphorylation of TSC2 and raptor. AMPK also phosphorylates and activates PGC-1α. mTORC1 itself can interact with PGC-1α and YY1 to stimulate transcription of mitochondrial genes. Finally, changes in cellular redox state, whether by changes in the NAD⁺/NADH ratio or increased oxidant production, can activate several redox signaling cascades. 1, Malate—γ-ketoglutarate transporter; 2, Glutamate—aspartate transporter; 3, Calcium uniporter; 4, Na⁺/H⁺ -dependent Ca²⁺ antiporter; 5, Adenine nucleotide translocator (ANT).