Can mitochondria with "depleted" mtDNA reproduce?

Question

Background

There's a popular group of antibiotics known as fluoroquinolones, abbreviated FQs. They're quinolone abx with a fluorine atom added at position 6 to increase cell permeability. Popular varieties of these drugs include ciprofloxacin, levofloxacin, norfloxacin, and many others. They also go by brand names Cipro, Levaquin, etc. They have a well known side effect of wreaking havoc on the body's mitochondria through numerous pathways.

This stunning image shows the in-vitro result of administering a clinically relevant dose of ciprofloxacin to human tissue for 24 hours (1). The study notes "short, swollen, fragmented mitochondria (smaller aspect ratio) with highly reduced branching (smaller form factor)"

Because the fluorine atom allows for deep tissue penetration, FQs can cross the double membrane of mitochondria, and because FQs are designed to target "double helix" DNA of some bacteria, they also appear capable of targeting the same double helix DNA structure in mitochondria. In bacteria, the FQs bind to the DNA-gyrase, causing breaks in the DNA that are fatal (2) to the bacteria.

Question

A study published in Molecular Pharmacology (3) shows that mtDNA is "depleted" by Cipro:

Analysis of mtDNA from ciprofloxacin-treated cells revealed the presence of site-specific, double-stranded DNA breaks. These results suggest that ciprofloxacin may be causing cytotoxicity by interfering with a mitochondrial topoisomerase II-like activity, resulting in a loss of mtDNA.

The full text of this study is not available as far as I can tell. I can find scientific literature on depletion of mtDNA (4) but what does this mean for the long term health of the mitochondria / cell?

1. Can mitochondria with "depleted" mtDNA reproduce, passing on the damage from breaks in the DNA? Or is the mitochondria and cell doomed?
2. More open ended: Is there any literature suggesting mitochondria damaged by oxidative stress can recover (first image), or are they also doomed?

References

1. Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells

2. Fluoroquinolones: Mechanisms of Action and Resistance

3. Delayed cytotoxicity and cleavage of mitochondrial DNA in ciprofloxacin-treated mammalian cells

4. Mitochondrial DNA metabolism targeting drugs

Answer 1

Can mitochondria with "depleted" mtDNA reproduce ?

If by depleted, you means reduced number of mtDNA copies, then yes, as long some copies still remain, these can be replicated.

Mitochondrial genome is replicated asynchroneously from nuclear genome [Bogenhagen, 1977], through a particular process (review [Holt, 2012]), and is present in multiple copies. These copies can be different, due to mutation.

Mitochondria do not "reproduce" in the common sense, as they do not undergo mitosis, but have a fission and fusion mechanism (review [van der Bliek, 2013]). The fission products get their half of the mtDNA copies at random when the two mitochondria separate.

Mitochondria with depleted mtDNA can (and do, according to your image) undergo fission.

passing on the damage from breaks in the DNA?

There are DNA repair mechanisms for the mitochondrial genome. In this case, the mechanism of choice to repair double strand break is microhomology-mediated end joining (MMEJ) [Tadi, 2016], that try to align the ends of the DSB through use of 5-25 bp homologuous sequence. This ususally results in the deletion of some material near the break.

The resulting mutation is conserved, and passed on through replication of this particular mtDNA instance. The mitochondria will contain a mix of mutated and non-mutated mtDNA from now on.

Or is the mitochondria and cell doomed?

One could say a particular mitochondria is "doomed" if there is no [viable] copy of mtDNA; if it is not able to maintain adequate internal membrane potential, it will try to fuse with other working mitochondria, or be eliminated through autophagy/mitophagy.

The cell itself could be "doomed" if there are not enough mitochondria left to meet energetic demands. (or, through mitochondria-induced aptotosis). Some particular human cell type have hypersensibility to fluroquinolones (tenocyte, chondrocyte, osteocyte), with increased cell death, but other types have not manifested this behaviour. [Barnhill, 2012] The reason for this sensibility/resistance is not elucidated.