Full reportMG-2610-4471Completed 23 Oct 2026, 14:31 UTC

FIS7 loss drives mitochondrial elongation and synaptic decline in aging cortical neurons

L. Okafor, M. Brandt, S. Iyer, J. Whitcombe

Field: Neuroscience · Cell biology
Length: 31 pp · 7,840 words
Figures: 6
References: 42
Target: eLife

Higher means a major revision or desk rejection is more likely.

Major: 4
Minor: 3
References flagged: 4

Summary

A clear, well-motivated study whose central claim currently outruns its evidence. Referees are likely to accept the imaging but ask for a rescue experiment, a culture-level reanalysis of the spine data, and either in vivo aging data or a narrower title.

Major concerns4

Likely to decide between minor and major revision. Address these first.

MajorCausal claimResults · Fig. 3

The causal claim rests on a single shRNA with no rescue

demonstrating that FIS7 is required for the maintenance of dendritic spines in mature neurons.

Why a reviewer will raise it: Every loss-of-function result in Fig. 3 uses one shRNA. Reviewers routinely ask whether the phenotype is off-target, and “required” is stronger than knockdown alone can support.
What to change: Re-express an shRNA-resistant FIS7 and show spine density recovers, or repeat the key panels with a second, independent shRNA or a CRISPR knockout. Until then, soften “required” to “contributes to”.

MajorStatisticsMethods · Fig. 2D

Neurons, not animals, are treated as independent replicates

n = 142 neurons from 3 cultures; p < 0.001, two-tailed t-test.

Why a reviewer will raise it: Neurons from the same culture are not independent. Pooling them inflates n and can turn a culture-level effect into an apparently strong one — a frequent reason for a major-revision request.
What to change: Report one value per culture (or per animal) and test on those, or fit a mixed-effects model with culture as a random effect. State the biological n in every legend.

MajorNoveltyIntroduction · ¶4

The novelty claim overlooks the Drp1 literature

This is the first report linking mitochondrial morphology to synaptic decline.

Why a reviewer will raise it: Links between fission machinery and synapse loss are well established for Drp1. A reviewer in this field will name those papers and question what is new here.
What to change: Cite the Drp1 work directly and state the specific advance — an FIS7-dependent, age-restricted mechanism — rather than a first-ever link.

MajorMissing experimentResults · Fig. 4–5

Aging is claimed in the title but tested only in culture

Together, these data establish FIS7 as a driver of synaptic decline during aging.

Why a reviewer will raise it: All aging data come from neurons kept 21 days in vitro. Reviewers will ask for at least one in vivo time point before accepting an aging claim.
What to change: Add FIS7 levels and spine counts from young and aged mouse cortex, or narrow the title and abstract to in-vitro maturation.

Minor concerns3

Quick to fix; editors notice them at triage.

MinorKey informationFig. 4 legend

Animal age and sex are missing from the Fig. 4 legend

Cortical tissue was collected and processed as described.

Why a reviewer will raise it: Most life-science journals require age and sex for every animal experiment; editors return manuscripts for this at triage.
What to change: Add age (in weeks) and sex for each group to the legend and the Methods.

MinorFiguresFig. 1B

Scale bars are absent from the confocal panels

Representative images of MitoTracker-labelled neurons.

Why a reviewer will raise it: Without scale bars, mitochondrial length cannot be judged from the images, which is the central measurement of the figure.
What to change: Add a scale bar to every micrograph and give its length in the legend.

MinorStatisticsFig. 3C

Western blot normalisation is not described

FIS7 protein was reduced by 68% relative to control.

Why a reviewer will raise it: Reviewers will ask which loading control was used and whether bands were within the linear range.
What to change: Name the loading control, show full blots in a supplement, and describe the quantification.

Reference check

42 references looked up in Crossref and Retraction Watch. Flagged entries are listed first.

38 verified · 1 retracted · 2 mismatch · 1 not found

Reference check results
Ref.	Citation	Status	Finding
[12]	Zhang H.-L. et al. Cell Rep 18, 1102⁠–⁠1115 (2017)doi:10.5555/celrep.2017.1102	Retracted	Retraction notice issued; check whether the claim it supports still stands.
[19]	Kowalski T. & Reyes A. J Neurosci 40, 512⁠–⁠527 (2020)doi:10.5555/jneuro.2020.0512	DOI mismatch	DOI points to a different paper by other authors.
[31]	Moreau P. Mitochondrion 58, 44⁠–⁠51 (2021)No DOI given	Not found	No record in Crossref under this title, journal or year.
[7]	Adeyemi K. et al. J Cell Sci 132, jcs2281 (2019)doi:10.5555/jcs.2019.2281	Verified	DOI resolves to the cited article.
[23]	Hallström R. et al. Neuron 102, 81⁠–⁠96 (2019)doi:10.5555/neuron.2019.0081	Verified	DOI resolves to the cited article.

This sample lists a selection of the 42 references.

Method note

Review passes: 2, independent
Raw findings: 11 → 7
Quotes discarded: 2
Model release: v0.3

This report is a pre-submission self-check. It does not judge whether the science is correct and does not guarantee acceptance.

Major concerns4

Likely to decide between minor and major revision. Address these first.

MajorCausal claimResults · Fig. 3

The causal claim rests on a single shRNA with no rescue

demonstrating that FIS7 is required for the maintenance of dendritic spines in mature neurons.

Why a reviewer will raise it: Every loss-of-function result in Fig. 3 uses one shRNA. Reviewers routinely ask whether the phenotype is off-target, and “required” is stronger than knockdown alone can support.
What to change: Re-express an shRNA-resistant FIS7 and show spine density recovers, or repeat the key panels with a second, independent shRNA or a CRISPR knockout. Until then, soften “required” to “contributes to”.

MajorStatisticsMethods · Fig. 2D

Neurons, not animals, are treated as independent replicates

n = 142 neurons from 3 cultures; p < 0.001, two-tailed t-test.

Why a reviewer will raise it: Neurons from the same culture are not independent. Pooling them inflates n and can turn a culture-level effect into an apparently strong one — a frequent reason for a major-revision request.
What to change: Report one value per culture (or per animal) and test on those, or fit a mixed-effects model with culture as a random effect. State the biological n in every legend.

MajorNoveltyIntroduction · ¶4

The novelty claim overlooks the Drp1 literature

This is the first report linking mitochondrial morphology to synaptic decline.

Why a reviewer will raise it: Links between fission machinery and synapse loss are well established for Drp1. A reviewer in this field will name those papers and question what is new here.
What to change: Cite the Drp1 work directly and state the specific advance — an FIS7-dependent, age-restricted mechanism — rather than a first-ever link.

MajorMissing experimentResults · Fig. 4–5

Aging is claimed in the title but tested only in culture

Together, these data establish FIS7 as a driver of synaptic decline during aging.

Why a reviewer will raise it: All aging data come from neurons kept 21 days in vitro. Reviewers will ask for at least one in vivo time point before accepting an aging claim.
What to change: Add FIS7 levels and spine counts from young and aged mouse cortex, or narrow the title and abstract to in-vitro maturation.

Minor concerns3

Quick to fix; editors notice them at triage.

MinorKey informationFig. 4 legend

Animal age and sex are missing from the Fig. 4 legend

Cortical tissue was collected and processed as described.

Why a reviewer will raise it: Most life-science journals require age and sex for every animal experiment; editors return manuscripts for this at triage.
What to change: Add age (in weeks) and sex for each group to the legend and the Methods.

MinorFiguresFig. 1B

Scale bars are absent from the confocal panels

Representative images of MitoTracker-labelled neurons.

Why a reviewer will raise it: Without scale bars, mitochondrial length cannot be judged from the images, which is the central measurement of the figure.
What to change: Add a scale bar to every micrograph and give its length in the legend.

MinorStatisticsFig. 3C

Western blot normalisation is not described

FIS7 protein was reduced by 68% relative to control.

Why a reviewer will raise it: Reviewers will ask which loading control was used and whether bands were within the linear range.
What to change: Name the loading control, show full blots in a supplement, and describe the quantification.

[12]

Zhang H.-L. et al. Cell Rep 18, 1102⁠–⁠1115 (2017)doi:10.5555/celrep.2017.1102

Retracted

Retraction notice issued; check whether the claim it supports still stands.

[19]

Kowalski T. & Reyes A. J Neurosci 40, 512⁠–⁠527 (2020)doi:10.5555/jneuro.2020.0512

DOI mismatch

DOI points to a different paper by other authors.

[31]

Moreau P. Mitochondrion 58, 44⁠–⁠51 (2021)No DOI given

Not found

No record in Crossref under this title, journal or year.

[7]

Adeyemi K. et al. J Cell Sci 132, jcs2281 (2019)doi:10.5555/jcs.2019.2281

Verified

DOI resolves to the cited article.

[23]

Hallström R. et al. Neuron 102, 81⁠–⁠96 (2019)doi:10.5555/neuron.2019.0081

Verified

DOI resolves to the cited article.