Computation of the mitochondrial age distribution along the axon length

2022

Preprint

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Mitochondria transport in a branched axon with two branches of different sizes is investigated; the results are compared with mitochondria transport in an axon with symmetric branches and in a straight (unbranched) axon. The interest in understanding mitochondria transport in branched axons is motivated by the large size of arbors of dopaminergic neurons, which die in Parkinson’s disease. Since the failure of energy supply of multiple demand sites located in various axonal branches may be a possible reason for the death of these neurons, we were interested in investigating how branching affects mitochondria transport. Besides investigating mitochondria fluxes between the demand sites and mitochondria concentrations, we also studied how the mean age of mitochondria and mitochondria age densities depend on the distance from the soma. We established that if the axon splits into two branches of unequal length, the mean ages of mitochondria and age density distributions in the demand sites are affected by how the mitochondria flux splits at the branching junction (what portion of mitochondria enters the shorter branch and what portion enters the longer branch). However, if the axon splits into two branches of equal length, the mean ages and age densities of mitochondria are independent of how the mitochondria flux splits at the branching junction. This even holds for the case when all mitochondria enter one branch, which is equivalent to a straight axon. Because the mitochondrial membrane potential (which many researchers view as a proxy for mitochondrial health) decreases with mitochondria age, the independence of mitochondria age on whether the axon is symmetrically branched or straight (providing the two axons are of the same length), and on how the mitochondria flux splits at the branching junction, may explain how dopaminergic neurons can sustain very large arbors and still maintain mitochondrial health across branch extremities.

Section: Resultsmentioning

confidence: 99%

“…Using the results reported in [29], ref. [17] estimated the age of mitochondria at the axon tip to be 22 hours. The mean ages of mitochondria reported in Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The same was done for the axon with two equal branches depicted in Fig.1b(Eqs. (1)-(15), and (S1)-(S3)) and for the straight axon depicted in Fig.1c(Eqs. (1)-(3), and (S12)-(S20)).…”

mentioning

confidence: 99%

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Effects of axon branching and asymmetry between the branches on transport, mean age, and age density distributions of mitochondria in neurons: a computational study

2022

Preprint

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“…1c). The model was obtained by extending the model of mitochondria transport reported in [16]. The mean age and age density distributions of mitochondria in various compartments were computed utilizing the methods developed in [17,18].…”

Section: Introductionmentioning

confidence: 99%

Effects of axon branching and asymmetry between the branches on transport, mean age, and age density distributions of mitochondria in neurons: A computational study

Numer Methods Biomed Eng

2022

Self Cite

We report a computational study of mitochondria transport in a branched axon with two branches of different sizes. For comparison, we also investigate mitochondria transport in an axon with symmetric branches and in a straight (unbranched) axon. The interest in understanding mitochondria transport in branched axons is motivated by the large size of arbors of dopaminergic neurons, which die in Parkinson's disease. Since the failure of energy supply of multiple demand sites located in various axonal branches may be a possible reason for the death of these neurons, we were interested in investigating how branching affects mitochondria transport. Besides investigating mitochondria fluxes between the demand sites and mitochondria concentrations, we also studied how the mean age of mitochondria and mitochondria age densities depend on the distance from the soma. We established that if the axon splits into two branches of unequal length, the mean ages of mitochondria and age density distributions in the demand sites are affected by how the mitochondria flux splits at the branching junction (what portion of mitochondria enter the shorter branch and what portion enter the longer branch). However, if the axon splits into two branches of equal length, the mean ages and age densities of mitochondria are independent of how the mitochondria flux splits at the branching junction. This even holds for the case when all mitochondria enter one branch, which is equivalent to a straight axon. Because the mitochondrial membrane potential (which many researchers view as a proxy for mitochondrial health) decreases with mitochondria age, the independence of mitochondria age on whether the axon is symmetrically branched or straight (providing the two axons are of the same length), and on how the mitochondria flux splits at the branching junction, may explain how dopaminergic neurons can sustain very large arbors and still maintain mitochondrial health across branch extremities.

Effect of mitochondrial circulation on mitochondrial age density distribution

2022

Preprint

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Recent publications report that although mitochondria population in an axon can be quickly replaced by combination of retrograde and anterograde axonal transport (often within less than 24 h), the axon contains much older mitochondria. This suggests that not all mitochondria that reach the soma are degraded, some of them participate in recirculation. To explain this we developed a model that simulates that a portion of mitochondria that return to the soma are redirected back to the axon rather than being destroyed in somatic lysosomes. Utilizing the developed model, we studied how the percentage of returning mitochondria affects the mean age and age density distributions of mitochondria at different distances from the soma. We also investigated whether turning off the mitochondria anchoring switch can reduce the mean age of mitochondria. For this purpose, we studied the effect of reducing the value of a parameter that characterizes the probability of mitochondria transition to the stationary (anchored) state. The reduction of the mean age of mitochondria observed when the chance of mitochondria to get anchored is reduced suggests that some injured neurons may be saved if the percentage of stationary mitochondria is decreased. Replacement of possibly damaged stationary mitochondria with newly synthesized ones may restore energy supply in an injured axon. We also performed a sensitivity study of the mean age of stationary mitochondria to the parameter that determines what portion of mitochondria re-enter the axon and the parameter that determines the probability of mitochondria transition to the stationary state.