Mitoplasticity: Adaptation Biology of the Mitochondrion to the Cellular Redox State in Physiology and Carcinogenesis

Abstract

Adaptation and transformation biology of the mitochondrion to redox status is an emerging domain of physiology and pathophysiology. Mitochondrial adaptations occur in response to accidental changes in cellular energy demand or supply while mitochondrial transformations are a part of greater program of cell metamorphosis. The possible role of mitochondrial adaptations and transformations in pathogenesis remains unexplored, and it has become critical to decipher the stimuli and the underlying molecular pathways. Immediate activation of mitochondrial function was described during acute exercise, respiratory chain injury, Endoplasmic Reticulum stress, genotoxic stress, or environmental toxic insults. Delayed adaptations of mitochondrial form, composition, and functions were evidenced for persistent changes in redox status as observed in endurance training, in fibroblasts grown in presence of respiratory chain inhibitors or in absence of glucose, in the smooth muscle of patients with severe asthma, or in the skeletal muscle of patients with a mitochondrial disease. Besides, mitochondrial transformations were observed in the course of human cell differentiation, during immune response activation, or in cells undergoing carcinogenesis. Little is known on the signals and downstream pathways that govern mitochondrial adaptations and transformations. Few adaptative loops, including redox sensors, kinases, and transcription factors were deciphered, but their implication in physiology and pathology remains elusive. Mitoplasticity could play a protective role against aging, diabetes, cancer, or neurodegenerative diseases. Research on adaptation and transformation could allow the design of innovative therapies, notably in cancer. Antioxid. Redox Signal. 18, 808–849.

I. Introduction

II. Definitions of Mitochondrial Adaptation to Acute or Persistent Redox Change, Mitochondrial Transformation, Metabolic Control, and Adaptative Loops

III. Mitochondrial Remodeling Pre-Exists in Most Cell Model Systems: Impact of the Culture Shock and the Bioenergetic Shock

IV. Cellular Energy Homeostasy Relies on the Coordination Between Glycolysis, OXPHOS and Direct Substrate Phosphorylation: Role of the AMPK

V. Mitochondrial Adaptation During Exercise Training, ER Stress, Genotoxic Stress, and Environmental or Biological Insults: Evidence of Immediate and Delayed Loops of Adaptation

VI. Mitochondrial Structural Adaptation Is Observed in Cancer Cells Confronted to Aglycemia

VII. The Rewiring of Pre-Existing Metabolic Routes Accommodates Energy Needs, Anabolic Needs, and ROS Management in Cancer Cells: Role of Hif1α, ChREBP, PDK, and PKM2

VIII. Cellular and Mitochondrial Adaptations to the Type of Available Energy Substrate: Ras and CC3 Modulate Metabolic Flexibility in Cancer Cells

IX. Compensation Without Adaptation: Safety Role of the Biochemical Threshold Effect and of Metabolic Attenuation

X. Mitochondrial Adaptative Loops in Response to Respiratory Chain Impairment: The AMPK-SIRT-PGC1-FOXO3 Pathway and the CREB Pathway

XI. Targeted Mitochondrial Protein Degradation: A Major Component of Mitoplasticity

XII. Role of ROS in Mitochondrial Adaptations in Physiology and Pathology

XIII. Conclusion