Retrograde mitochondrial transport is essential for mitochondrial homeostasis in neurons

Abstract

Mitochondrial transport in neurons is essential for forming and maintaining axonal projections. While much is known about anterograde mitochondrial movement, the function of retrograde mitochondrial motility in neurons was unknown. We investigated the dynamics and utility of retrograde mitochondrial transport. Using long-term tracking of mitochondria in vivo, we found mitochondria in axon terminals turnover within hours via retrograde transport. Mitochondria do not return to the cell body solely for degradation; rather, mitochondria use bidirectional transport to redistribute themselves throughout the neuron. Disruption of retrograde mitochondrial transport severely depletes the cell body of mitochondria and impacts mitochondrial health throughout the cell.Altered mitochondrial health correlates with decreased synaptic activity. Using proteomics, we provide evidence that retrograde mitochondrial movement functions to maintain the organelle's proteome. Together, our work demonstrates that mitochondrial retrograde transport is essential for the maintenance of a homeostatic population of mitochondria in neurons and consequently effective synaptic activity through promoting mitochondrial protein turnover. KeywordsMitochondria, Axonal Transport, Cytoplasmic dynein, Mitochondrial protein import, Retrograde transport, Dynactin, Actr10, p150 glued regulation of local translation 13,14 . Therefore, maintaining a healthy pool of mitochondria, particularly in distal compartments of the neuron, is critical for the health and maintenance of functional neural circuits. While much is known about how damaged mitochondria are cleared from this region [15][16][17] , less is known about how populations of healthy mitochondria are maintained in neurons over their lifetime.Mitochondrial maintenance is complicated by the fact that this organelle requires more than a thousand proteins for optimal health and function. While mitochondria maintain their own genome 18-20 , which includes genes encoding 13 proteins in humans, the bulk of the proteins important for the function and maintenance of this organelle are synthesized from genes encoded in the nucleus 21,22 . These proteins have diverse half-lives, ranging from hours to weeks 23,24 . Once generated, mitochondrial proteins translocate to the correct compartment within the organelle through well-described mitochondrial protein import pathways 25 . However, while we know how proteins are incorporated into the organelle, how they are brought to the organelle prior to import, particularly in distal compartments, is largely unknown. While transport of proteins and/or mRNAs could be sufficient to replenish a number of mitochondrial proteins, it would require active transport of individual components to organelles which can be a meter from the cell body in humans. Given the number of mitochondrial proteins, the rapid turnover rates of a subset of them, and the distance from the cell body to distal neuronal compartments, active transport of each individual protein would be energy intensive ...

Acquired disorders of mitochondrial metabolism and dynamics in pulmonary arterial hypertension

“…During cytokinesis, Miro-TRAK1/2-motor protein complexes recruit kinetochore protein F, which facilitates nuclear envelope breakdown, and enables anterograde movement of mitochondria towards the cell's cleavage furrow, potentially supplying ATP for contraction of the actomyosin ring (Lawrence and Mandato, 2013). Alternatively, mitochondria may associate with dynein and its activator dynactin for retrograde trafficking, allowing organellar degradation or their homogenous distribution throughout a cell, though to date, these functions have largely been explored in neurons (Mandal and Drerup, 2019;Mandal et al, 2021). Other inter-organellar associations, particularly the mitochondriaassociated membranes (MAMs) existing between mitochondria and the endoplasmic reticulum, are believed to be uniquely modulated by MFN2 (de Brito and Scorrano, 2008) and regulate calcium-mediated control over the cell cycle.…”

Importance of retrograde axonal transport in mitochondrial health and distribution

“…Recent work by Mandal et al significantly extended our understanding on the importance of retrograde mitochondrial transport in neurons and shed new lights on the consequence of disrupting this process on sensory and motor circuits in vivo 7 . The authors first visualise the distribution of fluorescently tagged mitochondria (mito-TagRFP) in vivo in zebrafish posterior lateral line (pLL) sensory neurons 8 carrying loss-of-function mutation in actr10 (actr10 nl15 ), which has previously been shown by Drerup et al to inhibit retrograde mitochondrial transport specifically without affecting the anterograde movement 9 .…”

Optimizing mitochondrial maintenance in extended neuronal projections

“…The fate of mitochondria when they reach the terminus of an axon may involve some combination of local degradation [56] and recirculation towards the soma [57][58][59].…”

“…This assumption is relaxed in the Changing-of-the-Guard model, where stationary mitochondria can restart in either the anterograde or retrograde direction. The fate of mitochondria when they reach the terminus of an axon may involve some combination of local degradation [56] and recirculation towards the soma [57–59]. Given that the retrograde and anterograge flux of mitochondria are similar in axons [32, 58, 60], we assume that most of the organelles return to the cell body for recycling.…”