Mitochondrial dynamics: the intersection of form and function

Abstract

Mitochondria within a cell exist as a population in a dynamic -morphological continuum. The balance of mitochondrial fusion and fission dictates a spectrum of shapes from interconnected networks to fragmented individual units. This plasticity bestows the adaptive flexibility needed to adjust to changing cellular stresses and metabolic demands. The mechanisms that regulate mitochondrial dynamics, their importance in normal cell biology, and the roles they play in disease conditions are only beginning to be understood. Dysfunction of mitochondrial dynamics has been identified as a possible disease mechanism in Parkinson's disease. This chapter will introduce the budding field of mitochondrial dynamics and explore unique characteristics of affected neurons in Parkinson's disease that increase susceptibility to disruptions in mitochondrial dynamics.

Fig. 2.1

Organellar and cellular controls of the mitochondrial life cycle. The mitochondria life cycle. (a) The mitochondria life cycle. Mitochondria go through continuous cycles of fusion and fission. Each cycle last 5–20 min. Fusion is brief (1) and triggers fission events (2). A daughter mitochondrion may maintain intact membrane potential (orange ) or depolarize (3, green). When depolarized a subsequent fusion event is unlikely to occur, unless the mitochondrial re-polarizes. As a result, depolarized daughter mitochondria remain solitary. Depolarized and solitary mitochondria (4) remain for 1–4 h in a pre-autophagic pool before being consumed by the autophagic machinery. (b) The interaction of the mitochondria life cycle with the cell cycle—this diagram depicts the normal life cycle of an individual mitochondrion during the G0 phase of the cell cycle. The mitochondrion undergoes fusion, fission, depolarization, and degradation by autophagy. This process is depicted as one of local control whereby mitochondrial events are largely dictated by the local energetic status and associated local signals. During the cell cycle global signals cause concerted changes in the mitochondrial population, as noted by hyperfusion in the G1-S and fragmentation during the M phase. These global population effects are governed by the cellular demand for energy required by cell division and the need for homogenization and sequestration of cellular components during met-phase. The cell cycle serves as an elegant example of the parities of local and global control

Fig. 2.1

Organellar and cellular controls of the mitochondrial life cycle. The mitochondria life cycle. (a) The mitochondria life cycle. Mitochondria go through continuous cycles of fusion and fission. Each cycle last 5–20 min. Fusion is brief (1) and triggers fission events (2). A daughter mitochondrion may maintain intact membrane potential (orange ) or depolarize (3, green). When depolarized a subsequent fusion event is unlikely to occur, unless the mitochondrial re-polarizes. As a result, depolarized daughter mitochondria remain solitary. Depolarized and solitary mitochondria (4) remain for 1–4 h in a pre-autophagic pool before being consumed by the autophagic machinery. (b) The interaction of the mitochondria life cycle with the cell cycle—this diagram depicts the normal life cycle of an individual mitochondrion during the G0 phase of the cell cycle. The mitochondrion undergoes fusion, fission, depolarization, and degradation by autophagy. This process is depicted as one of local control whereby mitochondrial events are largely dictated by the local energetic status and associated local signals. During the cell cycle global signals cause concerted changes in the mitochondrial population, as noted by hyperfusion in the G1-S and fragmentation during the M phase. These global population effects are governed by the cellular demand for energy required by cell division and the need for homogenization and sequestration of cellular components during met-phase. The cell cycle serves as an elegant example of the parities of local and global control

Fig. 2.2

The thermostat model of mitochondrial quality control. Separate pathways maintain mitochondrial homeostasis by safeguarding against functional extremes. In the cold extreme, PINK1 is stabilized within mitochondria upon membrane depolarization leading to increased kinase signaling. Alternatively, oxidative activation of cytosolic DJ-1 occurs in response to the hot extreme of excess ROS production. Downstream of both PINK1 and DJ-1 pathways is the recruitment of the E3 ligase Parkin and attachment of K63 and K48 polyubiquitin chains to mitochondrial outer membrane proteins. Damaged mitochondria are isolated and immobilized by proteasomal degradation of K48-tagged proteins, such as mitofusins and Miro. Proteasomal clearance of mitochondrial translocases prevents repopulation of the outer membrane with newly synthesized replacement proteins. Finally, K63 polyubiquitin chains selectively identifies mitochondria for autophagic clearance by recruitment of scaffold proteins, such as HDAC6 and p62