Mitochondrial respiratory quiescence: A new model for examining the role of mitochondrial metabolism in development

Abstract

Mitochondria are vital organelles with a central role in all aspects of cellular metabolism. As a means to support the ever-changing demands of the cell, mitochondria produce energy, drive biosynthetic processes, maintain redox homeostasis, and function as a hub for cell signaling. While mitochondria have been widely studied for their role in disease and metabolic dysfunction, this organelle has a continually evolving role in the regulation of development, wound repair, and regeneration. Mitochondrial metabolism dynamically changes as tissues transition through distinct phases of development. These organelles support the energetic and biosynthetic demands of developing cells and function as key structures that coordinate the nutrient status of the organism with developmental progression. This review will examine the mechanisms that link mitochondria to developmental processes. We will also examine the process of mitochondrial respiratory quiescence (MRQ), a novel mechanism for regulating cellular metabolism through the biochemical and physiological remodeling of mitochondria. Lastly, we will examine MRQ as a system to discover the mechanisms that drive mitochondrial remodeling during development.

Keywords: Cancer; Drosophila; Metabolism; Mitochondria; Oocytes; Quiescence; Reprogramming; Stem cells.

Figure 1. An outline of ATP production by the mitochondria.

This model depicts how inputs from the glycolysis and the fatty acid oxidation pathway feed the TCA cycle. This model also depicts how NADH and succinate produced by the TCA cycle drive ATP generation by the electron transport chain (ETC).

Figure 2. Mitochondria regulate biosynthesis, redox homeostasis, and cell signaling during development.

A) a model for how TCA intermediate feed the synthesis of lipids and amino acids. B) A model that depicts the two primary mechanisms (malate-aspartate shuttle and the glycerol phosphate shuttle) in the mitochondria that regenerate NAD⁺ in the cytosol and maintain cellular redox homeostasis. C) A diagram summarizing the signaling pathways regulated by mitochondria during development.

Figure 2. Mitochondria regulate biosynthesis, redox homeostasis, and cell signaling during development.

A) a model for how TCA intermediate feed the synthesis of lipids and amino acids. B) A model that depicts the two primary mechanisms (malate-aspartate shuttle and the glycerol phosphate shuttle) in the mitochondria that regenerate NAD⁺ in the cytosol and maintain cellular redox homeostasis. C) A diagram summarizing the signaling pathways regulated by mitochondria during development.

Figure 3. MRQ a new model to study mitochondrial remodeling during development.

A) A diagram that depicts the physiological changes that underlie cellular quiescence in development and in recurrent cancer. B) A model depicting the role of insulin/Akt/GSK3 signaling in the regulation of MRQ. C) A model highlighting how inducing MRQ promotes metabolic reprogramming in reproduction and models of cancer recurrence. In this model MRQ cause heritable changes in NAD⁺ that cause reduced levels methionine cycle production of SAM. These low levels of SAM cause reduced histone methylation, de-repression of gene expression, and promote the metabolic reprogramming of progeny and recurrence tumors.

Figure 3. MRQ a new model to study mitochondrial remodeling during development.

A) A diagram that depicts the physiological changes that underlie cellular quiescence in development and in recurrent cancer. B) A model depicting the role of insulin/Akt/GSK3 signaling in the regulation of MRQ. C) A model highlighting how inducing MRQ promotes metabolic reprogramming in reproduction and models of cancer recurrence. In this model MRQ cause heritable changes in NAD⁺ that cause reduced levels methionine cycle production of SAM. These low levels of SAM cause reduced histone methylation, de-repression of gene expression, and promote the metabolic reprogramming of progeny and recurrence tumors.