Abstract
SummaryCorrect mitochondrial distribution is critical for satisfying local energy demands and calcium buffering requirements and supporting key cellular processes. The mitochondrially targeted proteins Miro1 and Miro2 are important components of the mitochondrial transport machinery, but their specific roles in neuronal development, maintenance, and survival remain poorly understood. Using mouse knockout strategies, we demonstrate that Miro1, as opposed to Miro2, is the primary regulator of mitochondrial transport in both axons and dendrites. Miro1 deletion leads to depletion of mitochondria from distal dendrites but not axons, accompanied by a marked reduction in dendritic complexity. Disrupting postnatal mitochondrial distribution in vivo by deleting Miro1 in mature neurons causes a progressive loss of distal dendrites and compromises neuronal survival. Thus, the local availability of mitochondrial mass is critical for generating and sustaining dendritic arbors, and disruption of mitochondrial distribution in mature neurons is associated with neurodegeneration.
Highlights
Only 2% of the body’s weight, the brain consumes 20% of the body’s resting energy production (Harris et al, 2012), which may rise to 50% in the developing brain (Kuzawa et al, 2014)
Miro1 and Miro2 Have Different Roles for Animal Viability and Mitochondrial Trafficking To study the roles of Miro1 and Miro2, we characterized constitutive mouse knockout strains for Rhot1 (Miro1 gene) and Rhot2 (Miro2 gene) (Figures S1A–S1D) (Skarnes et al, 2011)
To address the specific roles of Miro1 and Miro2 for mitochondrial trafficking, we compared hippocampal neuronal cultures from individual wild-type (WT) or knockout E16 embryos generated by heterozygous (Miro1+/À X Miro1+/À or Miro2+/À X Miro2+/À) matings
Summary
Only 2% of the body’s weight, the brain consumes 20% of the body’s resting energy production (Harris et al, 2012), which may rise to 50% in the developing brain (Kuzawa et al, 2014). During brain development energy may be required to fuel the extensive neuronal growth necessary to build the complex neuronal morphologies (Kuzawa et al, 2014) that are essential for the formation of neuronal circuits (Jan and Jan, 2010) and for brain computation (Eyal et al, 2014; Spruston, 2008). The very large size of many neurons suggests that mitochondrial distribution must be spatially matched to local energy usage and calcium buffering requirements during the growth and maintenance of axons and dendrites. Mitochondrial distribution and trafficking may be key determinants for both the generation and the long-term maintenance of the complex neuronal morphologies essential for brain information processing (MacAskill and Kittler, 2010; Sheng and Cai, 2012). The relationship between mitochondrial distribution and the morphogenesis and maintenance of neuronal architecture in vivo remains unclear
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