Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

Abstract

The morphology of a population of mitochondria is the result of several interacting dynamical phenomena, including fission, fusion, movement, elimination and biogenesis. Each of these phenomena is controlled by underlying molecular machinery, and when defective can cause disease. New understanding of the relationships between form and function of mitochondria in health and disease is beginning to be unraveled on several fronts. Studies in mammals and model organisms have revealed that mitochondrial morphology, dynamics and function appear to be subject to regulation by the same proteins that regulate apoptotic cell death. One protein family that influences mitochondrial dynamics in both healthy and dying cells is the Bcl-2 protein family. Connecting mitochondrial dynamics with life-death pathway forks may arise from the intersection of Bcl-2 family proteins with the proteins and lipids that determine mitochondrial shape and function. Bcl-2 family proteins also have multifaceted influences on cells and mitochondria, including calcium handling, autophagy and energetics, as well as the subcellular localization of mitochondrial organelles to neuronal synapses. The remarkable range of physical or functional interactions by Bcl-2 family proteins is challenging to assimilate into a cohesive understanding. Most of their effects may be distinct from their direct roles in apoptotic cell death and are particularly apparent in the nervous system. Dual roles in mitochondrial dynamics and cell death extend beyond BCL-2 family proteins. In this review, we discuss many processes that govern mitochondrial structure and function in health and disease, and how Bcl-2 family proteins integrate into some of these processes.

Keywords: Apoptosis; Bcl-xL; Drp1; Mitochondria; Mitochondrial dynamics; Neurons.

Figure 1. Causal relationship between molecular machinery, mitochondrial dynamics and mitochondrial morphology

Schema summarizes the relationship between the underlying biochemical mechanisms that drive morphology through their effects on mitochondrial dynamics. Note that individual molecular species may in fact have multiple direct influences on dynamical phenomena.

Figure 2. Mitochondrial elongation is a conserved process across metazoans

Electron microscopy images of digestive gland cells from the bivalve molusc Ruditapes decussatus that was normally fed (A), or subjected to strict experimental starvation for 45 days (B). M: mitochondrion; Lu: lumen; Er: endoplasmic reticulum; G: Golgi apparatus; N: nucleus; GS: secretary granule; CF: flagellate cell. Scale bars: 1 μm (A); 2 μm (B).